Submissions for variant NM_000179.3(MSH6):c.188C>G (p.Ser63Cys)

gnomAD frequency: 0.00001  dbSNP: rs587779920

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459237	SCV000551105	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000572922	SCV000669940	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.S63C variant (also known as c.188C>G), located in coding exon 1 of the MSH6 gene, results from a C to G substitution at nucleotide position 188. The serine at codon 63 is replaced by cysteine, an amino acid with dissimilar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV000572922	SCV000685237	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 63 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has also been reported in a high-risk individual for pancreatic cancer, who had no personal history of cancer but a family history of breast/ovarian cancer (PMID: 30883245). This variant has been identified in 1/111686 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761153	SCV000891069	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.188C>G (p.Ser63Cys) missense change has a maximal subpopulation frequency of 0.0022% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-48010560-C-G). In silico tools are not in agreement about a tolerated or damaging effect on the gene or protein product and functional studies have not been performed. This variant has been reported in an individual with pancreatic cancer and a family history of breast and ovarian cancer (PMID: 30883245) and in an individual with endometrial cancer (PMID: 27443514). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
Myriad Genetics, Inc.	RCV003335336	SCV004043204	likely benign	Lynch syndrome 5	2023-08-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003463930	SCV004195642	uncertain significance	Endometrial carcinoma	2023-07-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000761153	SCV004830481	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 63 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). This variant has also been reported in a high-risk individual for pancreatic cancer, who had no personal history of cancer but a family history of breast/ovarian cancer (PMID: 30883245). This variant has been identified in 1/111686 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.