ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.835C>G (p.Leu279Val) (rs375351205)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122993 SCV000166288 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 279 of the MSH2 protein (p.Leu279Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs375351205, ExAC 0.006%). This variant has been reported in individuals affected with rectal cancer (PMID: 21056691), Lynch syndrome (PMID: 18566915), and breast cancer (PMID: 26976419). This variant has also been observed in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.835C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 135865). 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 RCV000131260 SCV000186225 likely benign Hereditary cancer-predisposing syndrome 2020-06-19 criteria provided, single submitter clinical testing Insufficient evidence;Other strong data supporting benign classification
GeneDx RCV000656875 SCV000292621 likely benign not provided 2021-04-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21056691, 18566915, 26976419, 27720647, 23729658)
Counsyl RCV000409770 SCV000488719 uncertain significance Lynch syndrome I 2016-05-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000237042 SCV000601491 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131260 SCV000685134 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces leucine with valine at codon 279 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with rectal cancer and the tumor had detectable MSH2 by immunohistochemistry (PMID: 21056691) and in a suspected Danish Lynch syndrome family (PMID: 18566915). This variant also has been reported in an individual affected with breast cancer with a BRCA2 p.Tyr1894* covariant (PMID: 26976419). This variant has been identified in 15/280528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000237042 SCV000917682 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.835C>G (p.Leu279Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 275108 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (5.1e-05 vs 0.00057), allowing no conclusion about variant significance. The variant, c.835C>G, has been reported in the literature in individuals affected with colorectal cancer (Limburg_Hepatol_2011, Nilbert_2009). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with other pathogenic variants (MLH1 c.117-1G>C; BRCA2 c.5682C>A, p.Tyr1894X) has been reported, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000409770 SCV001737484 uncertain significance Lynch syndrome I 2021-06-04 criteria provided, single submitter clinical testing The MSH2 c.835C>G (p.Leu279Val) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47641450-C-G). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in at least one individual with colorectal cancer (PMID: 18566915, 21056691) and one individual with breast cancer (PMID: 26976419). It has also been reported in a non-cancer control subject (PMID: 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656875 SCV001550480 uncertain significance not provided no assertion criteria provided clinical testing

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