ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1144+1G>A (rs373885654)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000149895 SCV000196743 likely pathogenic Lynch syndrome 2014-06-01 criteria provided, single submitter research
GeneDx RCV000213090 SCV000279941 pathogenic not provided 2017-03-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1144+1G>A or IVS10+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 10 of the PMS2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been observed in two individuals included in a population screening cohort, however personal and family cancer histories were not provided (Amendola 2015). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV001044002 SCV001207774 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-06-25 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs373885654, ExAC 0.02%). This variant has been observed in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 29566657). ClinVar contains an entry for this variant (Variation ID: 162508). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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