Submissions for variant NM_000251.3(MSH2):c.1831G>A (p.Val611Met)

gnomAD frequency: 0.00001  dbSNP: rs369385048

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000232146	SCV000284124	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-01	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 237376). This missense change has been observed in individual(s) with personal or family history of cancer (PMID: 31159747). This variant is present in population databases (rs369385048, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 611 of the MSH2 protein (p.Val611Met).
GeneDx	RCV000481079	SCV000567929	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of cancer who underwent genetic testing and additional clinical information was not provided (Tsaousis 2019); This variant is associated with the following publications: (PMID: 31159747, 18822302, 9774676, 21120944)
Ambry Genetics	RCV000575973	SCV000662227	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.V611M variant (also known as c.1831G>A), located in coding exon 12 of the MSH2 gene, results from a G to A substitution at nucleotide position 1831. The valine at codon 611 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported 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 one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575973	SCV000684982	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 611 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for hereditary cancer screening (PMID: 31159747). This variant has been identified in 1/246254 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.
Counsyl	RCV000662772	SCV000785573	uncertain significance	Lynch syndrome 1	2017-09-22	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000575973	SCV000822050	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662772	SCV004018232	uncertain significance	Lynch syndrome 1	2023-03-16	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003998756	SCV004829729	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 611 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for hereditary cancer screening (PMID: 31159747). This variant has been identified in 1/246254 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.