chr3-37008839-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS1
The NM_000249.4(MLH1):c.479C>T(p.Ala160Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A160S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.479C>T | p.Ala160Val | missense_variant | 6/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.479C>T | p.Ala160Val | missense_variant | 6/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000915 AC: 23AN: 251376Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135854
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461756Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49AN XY: 727198
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74426
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 11, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 10, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2021 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2017 | This variant is denoted MLH1 c.479C>T at the cDNA level, p.Ala160Val (A160V) at the protein level,and results in the change of an Alanine to a Valine (GCC>GTC). This variant was observed in at least one individualwith a personal history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). One in vitro functionalstudy showed mismatch repair activity and protein expression comparable to wild-type (Takahashi 2007). MLH1Ala160Val was observed at an allele frequency of 0.103% (17/16500) in individuals of South Asian ancestry in largepopulation cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). SinceAlanine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala160Valoccurs at a position that is not conserved and is located within the N-terminal ATPase domain (Andersen 2012). TheInternational Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertainbased on insufficient evidence for classification (Thompson 2014). In silico analyses are inconsistent regarding theeffect this variant may have on protein structure and function. Based on currently available evidence, it is unclearwhether MLH1 Ala160Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance - |
Lynch syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | - - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at