3-37012066-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000249.4(MLH1):āc.644A>Gā(p.Asn215Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251154Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135718
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461728Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727178
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
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. -
This missense variant replaces asparagine with serine at codon 215 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported that this variant had a normal DNA damage response in an MLH1-null human cell line (PMID: 30998989). This variant has been reported in an individual from a Lynch syndrome family (PMID: 18561205) and in an individual affected with peritoneum cancer (PMID: 30093976). This variant has been identified in 8/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
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Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
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Lynch syndrome Uncertain:1
This missense variant replaces asparagine with serine at codon 215 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported that this variant had a normal DNA damage response in an MLH1-null human cell line (PMID: 30998989). This variant has been reported in an individual from a Lynch syndrome family (PMID: 18561205 and the UMD database). This variant has been identified in 8/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates cell survival comparable to other known neutral variants in a methylation tolerance assay (PMID: 30998989); This variant is associated with the following publications: (PMID: 30093976, 26333163, 18561205, 22753075, 30998989) -
Hereditary nonpolyposis colon cancer Benign:1
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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