Submissions for variant NM_000179.3(MSH6):c.3664T>G (p.Phe1222Val)

dbSNP: rs775265464

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491642	SCV000580126	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-08	criteria provided, single submitter	clinical testing	The p.F1222V variant (also known as c.3664T>G), located in coding exon 8 of the MSH6 gene, results from a T to G substitution at nucleotide position 3664. The phenylalanine at codon 1222 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in conjunction with an APC mutation in a patient diagnosed with colon cancer at age 68 (Henn J et al. Hered Cancer Clin Pract. 2019 Jan;17:5). This variant was reported in 0/60,466 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 through reptiles. 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	RCV000491642	SCV000908428	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001370230	SCV001566697	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-03-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1222 of the MSH6 protein (p.Phe1222Val). This variant is present in population databases (rs775265464, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 428303). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268131	SCV002552357	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004802095	SCV005424979	uncertain significance	Lynch syndrome	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with valine at codon 1222 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial adenomatous polyposis (FAP) and colorectal cancer, who also carried an APC variant (PMID: 30680046). This variant has been identified in 1/251258 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.
GeneDx	RCV005230964	SCV005875154	uncertain significance	not provided	2024-08-25	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; Co-occurs with a pathogenic APC variant in a patient with a personal and family history of colorectal cancer (PMID: 30680046); This variant is associated with the following publications: (PMID: 17531815, 21120944, 12019211, 33471991, 30680046)