Submissions for variant NM_000251.3(MSH2):c.968C>T (p.Ser323Phe)

dbSNP: rs63750732

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166896	SCV000217713	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-04	criteria provided, single submitter	clinical testing	The p.S323F variant (also known as c.968C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 968. The serine at codon 323 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is not well 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.
Invitae	RCV000472836	SCV000548181	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000590192	SCV000566806	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Absent from cases but observed in controls in a breast cancer case-control study (PMID: 33471991); This variant is associated with the following publications: (PMID: 18822302, 21120944, 14635101, 27720647, 31552911, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000166896	SCV000690153	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 323 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 1/251446 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	RCV000590192	SCV000696295	uncertain significance	not provided	2017-06-05	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.968C>T (p.Ser323Phe) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121182 control chromosomes. The variant has been cited in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl	RCV000662856	SCV000785731	uncertain significance	Lynch syndrome 1	2017-11-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166896	SCV002526783	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662856	SCV004018273	uncertain significance	Lynch syndrome 1	2023-03-17	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.
PreventionGenetics, part of Exact Sciences	RCV004535130	SCV004116852	uncertain significance	MSH2-related disorder	2023-03-15	criteria provided, single submitter	clinical testing	The MSH2 c.968C>T variant is predicted to result in the amino acid substitution p.Ser323Phe. This variant has been reported in a study of NGS based multigene hereditary-cancer testing (Mu et al. 2016. PubMed ID: 27720647. Table S3). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47643460-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003995543	SCV004824498	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 323 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 1/251446 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.