NM_000179.3:c.3478G>T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000179.3(MSH6):c.3478G>T(p.Val1160Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727228
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Lynch syndrome 5 Pathogenic:1Uncertain:1
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. -
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Hereditary nonpolyposis colon cancer Pathogenic:1
Variant summary: MSH6 c.3478G>T (p.Val1160Phe) results in a non-conservative amino acid change located in the ATPase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3478G>T has been reported in the literature in at-least one individual affected with Lynch Like Syndrome (LLS) whose tumor demonstrated absent MSH6 protein staining by IHC analysis (Carwana_2021). This variant has also been observed in families with a personal and/or a family history of Lynch-related cancers tested at our laboratory (internal data). At-least one co-occurrence with other pathogenic variant(s) have been observed at our laboratory (BRIP1 c.2400C>G, p.Tyr800*) however, this is not weighted in the context of this evaluation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33215268). ClinVar contains an entry for this variant (Variation ID: 184794). Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1160 of the MSH6 protein (p.Val1160Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (LS) or LS-related cancers (Invitae). It has also been observed to segregate with disease in related individuals. Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 184794). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.V1160F variant (also known as c.3478G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3478. The valine at codon 1160 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been identified in several individuals whose Lynch syndrome-associated tumors demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at