Submissions for variant NM_000179.3(MSH6):c.2098C>A (p.Leu700Ile)

dbSNP: rs587779230

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218126	SCV000277014	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	The c.2098C>A (p.L700I) alteration is located in exon 4 (coding exon 4) of the MSH6 gene. This alteration results from a C to A substitution at nucleotide position 2098, causing the leucine (L) at amino acid position 700 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000684784	SCV000283741	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 700 of the MSH6 protein (p.Leu700Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 232785). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000232938	SCV000430968	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218126	SCV000904790	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 700 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 not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV002478805	SCV002802083	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-05-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000232938	SCV004843835	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 700 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 not been identified 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.