Submissions for variant NM_000179.3(MSH6):c.3988C>G (p.Leu1330Val)

dbSNP: rs768944975

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466998	SCV000551218	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775745	SCV000910176	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1330 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/246308 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.
Ambry Genetics	RCV000775745	SCV001183223	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.L1330V variant (also known as c.3988C>G), located in coding exon 9 of the MSH6 gene, results from a C to G substitution at nucleotide position 3988. The leucine at codon 1330 is replaced by valine, an amino acid with highly similar properties. This variant was previously detected in an individual diagnosed with breast cancer (Kaur RP et al. Med Oncol, 2018 Apr;35:81). 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.
GeneDx	RCV001555679	SCV001777133	uncertain significance	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast cancer in published literature (Kaur 2018); This variant is associated with the following publications: (PMID: 29700634)
Baylor Genetics	RCV003470467	SCV004195553	uncertain significance	Endometrial carcinoma	2023-08-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001844	SCV004835189	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1330 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/246308 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.