Mutation position in COSMIC

I am having trouble resolving genomic positions from COSMIC, as some mutations simply do not seem to match the reference nucleotides. For example, I am looking at this mutation:

http://cancer.sanger.ac.uk/cosmic/mutation/overview?id=1272062

It says that G mutated to A, but on that position in hg38 the base is A. Reverse complementing doesn't solve the problem (I know that COSMIC has strand specific entries).

Also, looking at the COSMIC browser representation, we see that the mutation starts one position earlier:

http://cancer.sanger.ac.uk/jbrowse/index.html?data=data%2Fjson%2Fgrch38%2Fv84%2Fcosmic&loc=1%3A2558433..2558486&tracks=cosmic_genes%2Cmutations%2Cbreakpoints&highlight=

All in all, I am thoroughly confused. The mutation is discovered in previous reference builds, so it persists, and there seems to be more of those. Anyone have an idea what is going on?

Thanks in advance!

cosmic vcf database

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updated 6.8 years ago by ramya.bio •

• written 8.5 years ago by ognjen011

It seems you discovered a bug :)

I checked on hg19 and it's looks like a G on this position but your gene doesn't exist on hg19 ... what a mess ..

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written 8.5 years ago by Titus

I have a similar issue. There are many COMIC mutations in my data which cannot be mapped to the reference. One example as below

COSM1000001 . It says G>A mutation at GRCh38, 19:51417106..51417106 position. But on this position the actual base is C. Please check this. On the same position, a dbsnp mutation occurs rs747638044 with C/A/T. The ensembl database also shows C as the ancestral base on this position. link.

Am I missing something here? I need to analyse the wild type and the mutated flanking sequences of these mutations. Please let me know how can I go forward in such cases.

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written 6.8 years ago by ramya.bio •

Apparently, this particular mutation is on the negative strand. That solves the problem.

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written 6.8 years ago by ramya.bio •

1 answer

Perhaps there are two things going on here:

Issue 1) allele A is the ancestral allele (perhaps we would expect it to be the derived allele); Issue 2) COSMIC shows the right genomic coordinate in their overview page i.e. 1:2558463, but not in the browser page i.e. 1:2558462-2558463.

If I were you, I'd get in touch with COSMIC re. the genomic coordinates reported by them in their browser view. This is not an indel, but rather a somatic SNV (single nucleotide variant).

Both gene and the somatic mutation are indeed reported on GRCh37 aka hg19. This is the genomic view of where the variant maps to the TNFRSF14 gene (note the allele A on the forward strand), and the variant specific page for [COSM1272062][4].

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written 8.5 years ago by Denise CS

I concord with Denise's first point. Please take a look at this previous answer by me: A: Alternate nucleotide is more frequent than reference nucleotide. OMG I'm dizzy.

The GRCh reference genomes, remember, are static and are in no way suitable references for all types of experiments. That said, having the reference genome is a huge benefit for researchers.

I know that COSMIC do their best but it's difficult to curate each and every variant. Even 1000 Genomes data is still in the process of being curated. Many of the somatic mutations in COSMIC may just be polymorphisms that have minimal roles in cancer and are just 'passenger' mutations.

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written 8.4 years ago by Kevin Blighe