rs375210430
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7
The NM_000179.3(MSH6):c.957G>A(p.Thr319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,866 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T319T) has been classified as Likely benign.
Frequency
Consequence
NM_000179.3 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.957G>A | p.Thr319= | synonymous_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.957G>A | p.Thr319= | synonymous_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251300Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135828
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461866Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2015 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 17, 2017 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 23, 2022 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 27, 2015 | 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MSH6 p.Thr319= variant was not identified in the literature nor was it identified in the Genesight-COGR, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in dbSNP (ID: rs375210430) as With Likely benign allele, ClinVar (classified as benign by GeneDx; classified as likely benign by Ambry Genetics, Invitae), Clinvitae (classified as likely benign by ClinVar), Cosmic (neutral (score 0.17) ), databases. The variant was identified in control databases in 7 of 246054 chromosomes at a frequency of 0.00003 in the following populations: SouthAsian in 3 of 30780 chromosomes (freq. 0.0001), European in 2 of 111556 chromosomes (freq.0.00002), Latino in 1 of 33574 chromosomes (freq. 0.00003), EastAsian in 1 of 17246 chromosomes (freq. 0.0001) increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr319= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at