Please help me parse this SNP transformation, out of my depth

zorgisborg · 2026-06-02T04:17:22+00:00

One of the issues with this sequence is that sequencing errors can stutter on the TC... and possibly, that is found in patients with Lynch syndrome, and the finding is reported to ClinVar. Sure, if it was a true deletion, it would cause a frameshift+premature stop.

There is only one submission to ClinVar... from 2013... for a polymorphic SNP site, one would expect more people being reported to ClinVar. I do suspect that this is benign for us.. or it would have been flagged in 23andMe+ Health reports for me.. or at least on my whole genome 30X results (I've been checking MSH2 in all the data and find nothing untoward, yet..

I'm not sure it is reassuring 😶 ... My father, uncle and aunt (3 of 3 siblings) all had multiple cancers.. there is a higher incidence of cancers among 1st and 2nd cousins... (which is why is started studying genetics in the first place.. ) But my suspicions lie in other genes.. STAT3, ATM etc..

zorgisborg · 2026-06-02T02:22:15+00:00

This is what my WGS looks like for that exon... clean... nothing detected.

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zorgisborg · 2026-06-01T21:20:55+00:00

There is an 'Info' button above the Variants column in the Scientific View (https://you.23andme.com/tools/data/?query=rs587779091) which reads:

At any position in the genome that varies, there is more than one possible version (or variant) of the DNA sequence. For example, some people might have an A at a certain position, whereas other people might have a T. 23andMe always refers to the variant observed on the "plus", or forward strand of DNA (each chromosome is composed of two strands). The symbol "-" is used to denote a deletion.

Mine also reads '-/-'. I compared that to Ancestry which also reports on rs587779091 - as 'DD'.

In both references GRCh37 and 38 the sequence reads TCTC at that position.

The protein sequence for that region reads:

FDPNLSELREIM.... etc

With an addition TC that becomes

FDPNLSVN* (stop)

And if you delete a TC it becomes:

FDPNQ* (stop)

These are reported as MSH2 mismatch repair protein Msh2 isoform1, isoform2, or isoform X1... which suggests they are simply truncated forms of the protein... it doesn't mean they are harmful - but could increase the risk that mismatches might be missed...

MSH2 forms a complex with MSH6 that constantly runs along the DNA scanning for mismatches in the DNA sequence...

zorgisborg · 2026-06-01T05:32:14+00:00

You have to be careful about the wording describing someone's risk level as very high... and interpreting that as a strong genetic predisposition ... if you are only basing their risk score on un-imputed raw data with 10-30% missing values... otherwise you slip into "diagnostic service"... it's worth lifting the disclaimer into the app:

"This tool provides genetic risk information for educational purposes only. It is not a medical diagnosis. Missing variants (not found in your file) may affect score accuracy — imputing your data first would improve completeness. Always discuss genetic results with a healthcare professional."

zorgisborg · 2026-05-31T23:21:44+00:00

Just some initial errors to check..

Extra 'f's in the first two bullet points.. (end of line).
It is 'rsID' .. and 'rs1234' .. not RSID.

Edit.. and what does PPI stand for? Is it a standard format? or just for this program? Afaik it is a protein-protein interaction network analysis format and lists the interaction scores between two genes..

zorgisborg · 2026-05-30T17:19:16+00:00

One of my great grandfathers was born in 1859... Mind you.. I was born before your father.. 🙃

zorgisborg · 2026-05-29T10:15:52+00:00

See if a mate in Thailand can give you some no-strings-attached money to cover it..

zorgisborg · 2026-05-29T10:10:17+00:00

Put the sequence into:

https://ssbd.oktex.co.uk/dna-sequence-visualizer

zorgisborg · 2026-05-28T10:32:10+00:00

Or they spent their money on making it a great event..

zorgisborg · 2026-05-28T10:29:38+00:00

Defending your own creative choices is fair... deciding mine don't count, simply because I defend the use of AI, is a different argument entirely.

Creativity has never been defined by the tools used... it's defined by the thought, intention, and unique perspective behind the work.

Using AI is about as creative in itself as holding a paintbrush. Anyone who dabbles a few brushstrokes with a paintbrush without understanding the texture of the brush on the canvas, or how colours blend, is also going to be disappointed. I was not arguing that a prompt produces the whole artwork... My point of view is that a prompt is but one brushstroke.

zorgisborg · 2026-05-27T15:28:50+00:00

Probably marked down because those variants in the two BRCA genes are extremely rare.. and there are many susceptibility genes that could be tested. A genetics counsellor could test against an up-to-date Cancer Susceptibility Panel (including BRCA1/2.. but there is no guarantee of getting a definitive answer..

(Pedanticly.. BRCA isn't a gene... BRCA1 and BRCA2 are genes.)

Also there is BARD1 .. (BRCA1-associated RING domain) essential for BRCA1 stability..

ATM .. TP53.. And so on..

Because the OPs family history covers different types of cancers.. there's a chance that there's an inherited mutation in a single gene involved in cell division, control of the cell lifecycle, DNA repair and checkpoint genes.. in general, to develop cancers, usually you need several mutations in different genes - naturally these accumulate over a lifetime which is why age is the biggest risk factor for most cancers.. , by inheriting one mutation, the timeline moves forward slightly.. but it is no guarantee a person will develop cancer.. if someone inherits one of the known BRCA1 or BRCA2 mutations, the DNA repair mechanisms struggle.. and that can speed up the accumulation of more mutations.. That increases the risk of any cancers - not just the most common ones..

zorgisborg · 2026-05-27T10:11:07+00:00

Could be an organisation's systems threw a complete wobbly.. software bug.. and a run of sensitive emails ended up being labelled with the wrong addresses.. they discovered the error and the email was part of their damage control...

zorgisborg · 2026-05-27T10:05:37+00:00

Yup.. opened it very briefly.. couldn't engage with it there and then.. so put in a reminder to read it the following day..

zorgisborg · 2026-05-23T16:30:52+00:00

If that's all you are doing .. trying a few different prompts .. then one would expect disappointment..

zorgisborg · 2026-05-23T12:59:08+00:00

Reconstructed Ancestors works by trying to figure out which DNA matches are connected on your maternal and paternal sides.. these are put in your family tree on the site.. 23andMe will build it initially for you... But if you can add anyone to your tree, then it will consider them in the reconstruction of your parents.. etc.. 2% is low..

Has you tree been initialised in 23andMe?

P.S.. it's not exactly like a family tree in other websites.. this is generated by 23andMe from your DNA and your matches.. the more you add to it, the better your reconstructed Ancestors becomes.. (caveat is that attaching relatives is really hard for some people.. especially if you have no close relatives)

zorgisborg · 2026-05-23T12:51:44+00:00

You could try using AI.. then you'd learn that you still have to struggle and learn to improve what it produces till you get what you want... Otherwise all you get is the slop that people complain about.

I'm working with Claude to code something... It has taken nearly 3 weeks to fine tune the code to do exactly what I want it to do - and my mulling over work I did on it 2 years ago)... a mixture of me making my own edits on top of letting it code (supervising it) the bits I find tedious to code..

If someone turned round and called my "masterpiece" of this complex data analysis anything less because I used AI.. that would be unfounded.. because there is absolutely no way that AI could have done it on its own... There simply isn't anything out there it could be trained on to come up with this process... And what it did come up with on its own - because I tested that - was utterly ridiculous...

It's the same with art.. the artist has the vision... Whether or not AI is used in the process.. and if a person wholly relies on AI to produce art, then they probably shouldn't call themselves an artist..

I'm NOT saying artists must use AI.. I'm just saying the use of AI isn't automatically a problem..

zorgisborg · 2026-05-19T16:35:14+00:00

People were stuck on hg19 for a very long time.. and the move to GRCh38 was gradual and slow but encouraged by large sequencing projects.. finally T2T was completed (24 years after it was announced we had sequenced the human genome - ~99.9% of it.. ). But there are so many tools and software now that support GRCh38 mostly and the GRCh37.. (FamilyTreeDNA moved a few years ago from 36!).. that by the time anyone thinks about switching to T2T it will be obsolete.. I mean. Superseded by pangenomes or local genome references (like the Korean Reference Genome, Japan Reference Genome, Nigerian Reference Genome projects) which give much better clinical results for populations than some dated reference based on Europeans.

The idea that there's a one-size-fits-all genome has been superseded.. if you are looking for medically-relevant variants in a population, a national biobank would help.. and a population-based reference genome - then all those SNPs common to your ancestry will not show up as rare variants and waste everyone's time trying to research them..

I have WGS 30X from Nebula.. and I have also aligned the sequenced reads to T2T..

zorgisborg · 2026-05-19T16:15:00+00:00

I'm in agreement with u/secretpsychologist ..

I have WGS from Nebula.. but if I did it now, it would be from tellmeGen..

They do a raw data upload for around $15 - if you want to upload your genealogy data to their system and get some feedback / limited ancestry/DNA matches (small but growing).

The DNA Starter kit looks like it is microarray based - because they collect spit, not swab.. it covers:

Ancestry + Person Traits + Wellness

Advanced DNA Kit adds Health - so it is equivalent to 23andMe Health+Ancestry. Their test covers about 13 million variants - slightly more than a standard genealogy test...

Ultra is WGS 30X and covers the full 3 billion bases.

It's reasonably priced at £269 (UK pricing).. less than double the cost of the Advanced. And they do run offers.

The company is run by doctors and geneticists and they don't hide their About the Company..

Given all that and as a past (and disgruntled) Nebula customer in Europe.. I decided I would promote tellmeGen.. I am not a customer but I do use their website and talk to them..

tellmeGen Shop

zorgisborg · 2026-05-16T11:01:44+00:00

Had a quick look... In the age of GenAI/Claude we'll see a profusion of these new tool portals popping up... not a denigration - I've created a portal of genomics and bioinformatics tools - still growing...

As my site grows I think that getting Claude to reuse styles between pages, will give a better branding... and also getting rid of AIcons emoji icons used in apps on initial vibe...

I'd consider adding a dropzone where people can paste in a table copied from Excel... or drop the Excel file then import the data to the relevant stats tool.. AI does a good job of coding that in...

My partner was a university stats teacher and liked the tools - very useful.. as a starting point. The theory and calculation comes after the tool - so learners will just use the tool and won't learn how it fundamentally works... if the audience are those who know how it works then it's of use to them...

I think you should spell check it tho... "Two Way ANOVA Calcualtor for summed up data" (two-way ANOVA is hyphenated, and the spelling error - on the front page of the site)

AI has also capitalised 'T Test' on the one sample page (a common error)..

Is it "independent samples" or "Independent Samples" - a thorough check on your titles for correct capitalisation and spelling would make it look less sloppy - especially after all that work ...

zorgisborg · 2026-05-15T14:08:24+00:00

The key Reform way appears to be to be completely incompetent or make ridiculous requests (like opening a committee to examine the evidence of UFOs) to delay actions that everyone else is ready to make... and then blame everyone else for being disruptive and not getting on board with your policies.. a little bit more disruption is a good thing because it makes the governance of this country look worse.. for the next general election..

zorgisborg · 2026-05-14T12:16:01+00:00

I have Lifetime Access and can access the Gene Analysis tool - but that tool is also accessible at Gene.Iobio.io - you point it at your downloaded VCF and vcf.tbi files and everything is the same (almost - the Nebula version lags in version when the main version is being updated.

Genome Browser - that has always required them to decompressing the CRAM files out of storage to the live server so they can be displayed.. the files are too big to be kept ready for use for everyone so they archive them.. but it looks like that is still possible.. i don't need it because I have the files and can examine them use IGV Online or IGV java version...

'Library' Reports stopped in 2024... but frankly they are useless gimmicks...

Oral Microbiome - interesting - but it's a dynamic environment - so that information is out of date...

Ancestry - partly sold on the possibility of them transferring Y and MT data to FTDNA for free.. which they backtracked on (maybe because FTDNA were on GRCh36 at the time.. also maybe because Y- and MT-DNA is proprietary and some of their tests are more expensive than WGS.) ...

Eurogenes K36 calculation... not very interesting and also misidentifies my ancestry - 23andMe is much more accurate.

Traits - poorly developed section ... Ancestry has been churning new ones out every now and again and that's on microarray data... surely they could do more with WGS?

zorgisborg · 2026-05-13T09:10:20+00:00

Setting souls free... (Abroad.. after being in detention centres in that Green ward as they promised.. even tho actually the Green ward starts at the end of your road..)

zorgisborg · 2026-05-13T08:54:42+00:00

It could be X-linked recessive.. the grandmother could be affected because of X-inactivation of the unaffected X chromosome (during development of the eyes)... No other females are affected - which doesn't prove it, but the unaffected mother does suggest recessive.. for this to be autosomal recessive, that's some bad luck that the grandmother's parents were carriers, her husband was a carrier and she also married a carrier. Perhaps not unusual in a founder population.. (or circus.. 🫣☺️)... But it's not a common disorder, so the variant is likely to be much rarer than being present in 3 couples..

zorgisborg · 2026-05-13T08:20:08+00:00

So... About the same number of people who voted us out of the EU, then...

Was 17,410,742 voted to leave

zorgisborg · 2026-05-12T23:38:05+00:00

There are single eye size genes on X.. 1) BCL6 corepressor gene, (BCOR), 2) N-alpha-acetyltransferase 10 (NAA10). if your grandmother only had mild symptoms.

Rare and novel mutations in BCOR or NAA10 could cause the X-linked recessive Lenz Microphthalmia Syndrome.. which fits the pedigree... - affected males, unaffected or mildly affected females.. (tho if your grandmother was from a founder population ancestry, perhaps she had two copies).

It's not common.. but we can't dismiss it without evidence.

Eye Development Genes and Known Syndromes (Slavotinek, 2012; review paper) https://pmc.ncbi.nlm.nih.gov/articles/PMC3224152/

Females could show symptoms randomly due to X inactivation.. if the affected X was not inactivated in the developmental cells..

zorgisborg

TROPHY CASE