ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.962T>C (p.Val321Ala) (rs186448384)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206591 SCV000259945 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 321 of the PMS2 protein (p.Val321Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs186448384, ExAC 0.03%). This variant has been observed in an individual affected with colorectal cancer (PMID: 30521064). ClinVar contains an entry for this variant (Variation ID: 219846). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000213107 SCV000274557 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000213107 SCV000686261 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588695 SCV000697405 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The c.962T>C (p.Val321Ala) in PMS2 gene is a missense variant involves a highly conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant is located within Conserve mismatch repair protein domain, although no experimental data suggesting the impact of the variant on the protein function have been reported at the time of evaluateion. The variant is present in the control population datasets of ExAC and gnomAD at a similar frequencies of 0.000029 (3/ 120276 and 8/277040 chrs tested), exclusively in individuals of East Asian descent (0.00035; 3/8642 and 0.00042; 8/18868 chrs tested, respectively). These frequencies exceed the maximal expected allele frequency for a non-common pathogenic variant (0.00011), suggesting that c.962T>C is an ethnic-specific polymorphism. The BLAST analysis confirmed that the variant is likely to be PMS2-derived. The variant has not, to our knowledge, been reported in affected individuals via published reports, but is cited as VUS by a reputable database/clinical laboratories. Taken all together, the variant was classified as VUS until more data becomes available.
Counsyl RCV000662446 SCV000784914 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-02-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000588695 SCV000806229 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093690 SCV001250874 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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