Submissions for variant NM_000179.3(MSH6):c.41C>T (p.Ser14Phe)

dbSNP: rs863224628

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196789	SCV000254326	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575547	SCV000662516	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	The p.S14F variant (also known as c.41C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 41. The serine at codon 14 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000575547	SCV000685488	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 14 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 1/244750 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.
Counsyl	RCV000662898	SCV000785818	uncertain significance	Lynch syndrome 5	2017-12-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001564528	SCV001787707	uncertain significance	not provided	2023-03-06	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 breast cancer (Tung et al., 2016); This variant is associated with the following publications: (PMID: 22949387, 23729658, 26976419)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150088	SCV003838312	uncertain significance	Breast and/or ovarian cancer	2022-11-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662898	SCV004018940	uncertain significance	Lynch syndrome 5	2023-03-28	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	RCV003462323	SCV004195570	uncertain significance	Endometrial carcinoma	2023-08-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997002	SCV004832288	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 14 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 1/244750 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.