Submissions for variant NM_000179.3(MSH6):c.3505C>G (p.Pro1169Ala)

gnomAD frequency: 0.00001  dbSNP: rs904846776

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543217	SCV000624876	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572853	SCV000662447	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-21	criteria provided, single submitter	clinical testing	The p.P1169A variant (also known as c.3505C>G), located in coding exon 6 of the MSH6 gene, results from a C to G substitution at nucleotide position 3505. The proline at codon 1169 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588973	SCV000695871	uncertain significance	not provided	2016-03-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000572853	SCV001346697	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1169 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251340 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588973	SCV001469568	uncertain significance	not provided	2020-07-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000588973	SCV002008473	uncertain significance	not provided	2023-07-25	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949379, 21120944, 17531815)
Baylor Genetics	RCV003470704	SCV004197584	uncertain significance	Endometrial carcinoma	2024-03-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003694	SCV004835078	uncertain significance	Lynch syndrome	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1169 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251340 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.