Submissions for variant NM_000179.3(MSH6):c.3341T>A (p.Leu1114Gln)

dbSNP: rs1553331600

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566943	SCV000669979	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The p.L1114Q variant (also known as c.3341T>A), located in coding exon 5 of the MSH6 gene, results from a T to A substitution at nucleotide position 3341. The leucine at codon 1114 is replaced by glutamine, an amino acid with dissimilar 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586719	SCV000695861	uncertain significance	not provided	2016-08-24	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3341T>A (p.Leu1114Gln) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121370 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000813407	SCV000953766	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1114 of the MSH6 protein (p.Leu1114Gln). 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: 483799). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483532	SCV002792950	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-08-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566943	SCV004357713	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 1114 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.
All of Us Research Program, National Institutes of Health	RCV004001055	SCV004835052	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 1114 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.