Submissions for variant NM_000179.3(MSH6):c.3529C>G (p.Leu1177Val)

gnomAD frequency: 0.00001  dbSNP: rs748398941

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469909	SCV000551098	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000521217	SCV000618484	uncertain significance	not provided	2017-05-25	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3529C>G at the cDNA level, p.Leu1177Val (L1177V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a breast tumor (Gellert 2016). MSH6 Leu1177Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1177Val occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Leu1177Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568727	SCV000669922	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-28	criteria provided, single submitter	clinical testing	The p.L1177V variant (also known as c.3529C>G), located in coding exon 6 of the MSH6 gene, results from a C to G substitution at nucleotide position 3529. The leucine at codon 1177 is replaced by valine, an amino acid with highly similar properties. This variant was present with a carrier frequency of 0.00299 in 1005 Japanese pancreatic cancer patients and with a carrier frequency of 0.00025 in 23705 controls (Mizukami K et al. EBioMedicine, 2020 Oct;60:103033). This alteration was also identified in an individual diagnosed with an upper tract urothelial carcinoma (Guan B et al. Front Oncol, 2022 Mar;12:774202). 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.
Counsyl	RCV000663017	SCV000786035	uncertain significance	Lynch syndrome 5	2018-02-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568727	SCV001341544	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1177 of 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 been reported in an individual affected with urothelial carcinoma and suspected of Lynch syndrome (PMID: 35372080). Additionally, in a pancreatic cancer case-control study this variant has been reported in 3/1005 cases and 6/23705 unaffected controls (PMID: 32980694), and in a large breast cancer case-control study this variant has been reported in 1/60466 cases and 6/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD) with all three variant alleles detected in the East Asian population. 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.
Myriad Genetics, Inc.	RCV000663017	SCV004018455	uncertain significance	Lynch syndrome 5	2023-03-27	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	RCV003463928	SCV004197702	uncertain significance	Endometrial carcinoma	2023-09-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001826	SCV004835085	uncertain significance	Lynch syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1177 of 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 been reported in an individual affected with urothelial carcinoma and suspected of Lynch syndrome (PMID: 35372080). Additionally, in a pancreatic cancer case-control study this variant has been reported in 3/1005 cases and 6/23705 unaffected controls (PMID: 32980694), and in a large breast cancer case-control study this variant has been reported in 1/60466 cases and 6/53461 unaffected controls (PMID: 33471991). This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD) with all three variant alleles detected in the East Asian population. 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.