Submissions for variant NM_000179.3(MSH6):c.4068G>C (p.Leu1356Phe)

gnomAD frequency: 0.00001  dbSNP: rs192740549

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212694	SCV000211333	uncertain significance	not provided	2023-05-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17531815, 21120944, 12019211)
Ambry Genetics	RCV000160704	SCV000216505	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.L1356F variant (also known as c.4068G>C), located in coding exon 10 of the MSH6 gene, results from a G to C substitution at nucleotide position 4068. The leucine at codon 1356 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not 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.
Invitae	RCV000168081	SCV000218735	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160704	SCV000690439	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1356 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/282124 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	RCV000662520	SCV000785072	uncertain significance	Lynch syndrome 5	2017-04-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662520	SCV004018925	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330517	SCV004038277	uncertain significance	not specified	2023-08-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998507	SCV004835205	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 1356 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/282124 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.