Submissions for variant NM_000251.3(MSH2):c.1597C>G (p.Leu533Val)

gnomAD frequency: 0.00001  dbSNP: rs786202987

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166086	SCV000216849	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	clinical testing	The p.L533V variant (also known as c.1597C>G), located in coding exon 10 of the MSH2 gene, results from a C to G substitution at nucleotide position 1597. The leucine at codon 533 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In another study, this variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000166086	SCV000684951	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 533 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a large breast cancer case-control study in one affected individual and one healthy control (PMID: 33471991), as well as in an individual undergoing genetic testing for hereditary cancer (PMID: 31159747). This variant has not been identified 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.
Invitae	RCV000689634	SCV000817295	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 533 of the MSH2 protein (p.Leu533Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of hereditary cancer (PMID: 31159747, 34284872). ClinVar contains an entry for this variant (Variation ID: 186484). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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.
GeneKor MSA	RCV000166086	SCV000822045	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761063	SCV000890978	uncertain significance	Lynch syndrome	2020-10-14	criteria provided, single submitter	clinical testing	The MSH2 c.1597C>G (p.Leu533Val) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; http://gnomad.broadinstitute.org). Five of seven in silico tools predict a damaging effect on the gene or protein product (PP3), however these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.