Submissions for variant NM_000179.3(MSH6):c.2117T>C (p.Phe706Ser)

dbSNP: rs587779231

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074718	SCV000107926	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854277	SCV002299340	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-12-17	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt MSH6 protein function. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 28531214, 17453009). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89254). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 706 of the MSH6 protein (p.Phe706Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137606	SCV003806889	likely pathogenic	Lynch syndrome 5	2022-08-11	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PP3 supporting
Myriad Genetics, Inc.	RCV003137606	SCV004189304	likely pathogenic	Lynch syndrome 5	2023-08-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28531214]. This variant is expected to disrupt protein structure [Myriad internal data].
Color Diagnostics, LLC DBA Color Health	RCV003584540	SCV004357633	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with serine at codon 706 of the MSH6 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). Functional studies have shown that this variant results in decreased protein expression of MSH2 and MSH6, increased microsatellite instability, and increased sensitivity to DNA damage agents in mouse embryonic stem cells (PMID: 28531214). This variant has been reported in an individual affected with colorectal cancer showing loss of MSH6 protein via immunoshistochemistry and who had a family history of Lynch syndrome-associated disease (PMID: 17117178). Of note, this individual also carried a pathogenic variant in the BRCA2 gene. This variant has also been observed in an individual with a Lynch syndrome-associated cancer with high microsatellite instability and who had family history of Lynch syndrome (PMID: 28531214), as well as an individual affected with breast and/or ovarian cancer (PMID: 27153395). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530136	SCV001744832	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530136	SCV001960020	likely pathogenic	not provided		no assertion criteria provided	clinical testing