chr2-47783427-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_000179.3(MSH6):c.194C>T(p.Ser65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 1,506,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S65A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.194C>T | p.Ser65Leu | missense_variant | 1/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.194C>T | p.Ser65Leu | missense_variant | 1/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000181 AC: 2AN: 110704Hom.: 0 AF XY: 0.0000162 AC XY: 1AN XY: 61788
GnomAD4 exome AF: 0.0000281 AC: 38AN: 1354564Hom.: 0 Cov.: 34 AF XY: 0.0000240 AC XY: 16AN XY: 666208
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74296
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 08, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 02, 2023 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 14, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer; however, analysis of this tumor revealed presence of MLH1, MSH2, and MSH6 proteins by immunohistochemistry and microsatellite stable histology (Barnetson et al., 2008); This variant is associated with the following publications: (PMID: 19389263, 24728327, 27527004, 21153778, 22290698, 23621914, 29641532, 18033691) - |
Lynch syndrome Benign:1
Likely benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability 0.001-0.049 - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at