Submissions for variant NM_000179.3(MSH6):c.3833C>G (p.Pro1278Arg)

dbSNP: rs201191389

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412068	SCV000488083	uncertain significance	Lynch syndrome 5	2015-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000034499	SCV000618315	uncertain significance	not provided	2022-06-10	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; Observed in an individual with atherosclerosis, with no specific information about cancer history (Johnston 2012); This variant is associated with the following publications: (PMID: 22703879, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000583219	SCV000690411	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This variant is located in the MSH6 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 MSH6-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812999	SCV000953331	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1278 of the MSH6 protein (p.Pro1278Arg). 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: 41594). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000583219	SCV002621645	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-06	criteria provided, single submitter	clinical testing	The p.P1278R variant (also known as c.3833C>G), located in coding exon 9 of the MSH6 gene, results from a C to G substitution at nucleotide position 3833. The proline at codon 1278 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108). 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.
Myriad Genetics, Inc.	RCV000412068	SCV004019100	uncertain significance	Lynch syndrome 5	2023-03-30	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.
Baylor Genetics	RCV003460542	SCV004195720	uncertain significance	Endometrial carcinoma	2023-06-20	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034499	SCV000043362	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.