rs368059229
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1
The NM_000179.3(MSH6):c.1917G>A(p.Glu639Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000179.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251038Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135710
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461866Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16AN XY: 727226
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74348
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
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This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
The synonymous variant NM_000179.3(MSH6):c.1917G>A (p.Glu639=) has been reported to ClinVar as Benign/Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 183801 as of 2025-01-02). The p.Glu639= variant is not predicted to disrupt an existing splice site. The p.Glu639= variant is predicted to introduce a novel splice site by 1 of 4 splice site algorithms. The p.Glu639= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Likely Benign. -
Lynch syndrome Benign:2
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not provided Benign:2
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Variant summary: The MSH6 c.1917G>A variant affects a non-conserved nucleotide, resulting in no amino acid change. One in-silico tool predicts damaging outcome for this variant, and 2/5 Alamut algorithms predict a change in a cryptic splice acceptor site. This variant was found in 7/120720 control chromosomes at a frequency of 0.000058, which does not significantly exceed maximal expected frequency of a pathogenic MSH6 allele (0.0001421). However, the variant was predominantly found in East Asians, at an allele frequency of 0.0006935, which is significantly greater than the maximal expected allele frequency, suggesting this may be a benign polymorphism in East Asians. In addition, several clinical laboratories classified this variant as likely benign without evidence to independently evaluate. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as likely benign until additional information is available. -
not specified Benign:1
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at