Submissions for variant NM_000251.3(MSH2):c.2661C>G (p.Phe887Leu)

gnomAD frequency: 0.00001  dbSNP: rs1290935051

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526536	SCV000625402	benign	Hereditary nonpolyposis colorectal neoplasms	2023-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193289	SCV001362024	uncertain significance	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2661C>G (p.Phe887Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251088 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2661C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV002289718	SCV002580175	uncertain significance	Lynch syndrome 1	2022-08-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431522	SCV002743498	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-13	criteria provided, single submitter	clinical testing	The p.F887L variant (also known as c.2661C>G), located in coding exon 16 of the MSH2 gene, results from a C to G substitution at nucleotide position 2661. The phenylalanine at codon 887 is replaced by leucine, an amino acid with highly similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV004003750	SCV004838233	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 887 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 3/251088 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002289718	SCV005689138	uncertain significance	Lynch syndrome 1	2025-02-05	criteria provided, single submitter	clinical testing	The MSH2 c.2661C>G (p.Phe887Leu) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.