Submissions for variant NM_000179.3(MSH6):c.3969T>G (p.Phe1323Leu)

dbSNP: rs1057520473

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480171	SCV000567800	uncertain significance	not provided	2018-03-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3969T>G at the cDNA level, p.Phe1323Leu (F1323L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe1323Leu was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain and the binding site of MSH2 (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Phe1323Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001021548	SCV001183175	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	The p.F1323L variant (also known as c.3969T>G), located in coding exon 9 of the MSH6 gene, results from a T to G substitution at nucleotide position 3969. The phenylalanine at codon 1323 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262331	SCV001440155	uncertain significance	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001350960	SCV001545388	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1323 of the MSH6 protein (p.Phe1323Leu). This variant is not present in population databases (gnomAD no frequency). 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: 419767). 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 MSH6 protein function with a negative predictive value of 95%. 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.
Baylor Genetics	RCV003464001	SCV004195685	uncertain significance	Endometrial carcinoma	2023-07-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002313	SCV004821997	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing