chr3-37004469-A-G
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1
The NM_000249.4(MLH1):c.375A>G(p.Ala125Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,613,700 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_000249.4 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: 0.000650 AC: 99AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000609 AC: 153AN: 251398Hom.: 0 AF XY: 0.000567 AC XY: 77AN XY: 135862
GnomAD4 exome AF: 0.000515 AC: 753AN: 1461336Hom.: 0 Cov.: 30 AF XY: 0.000502 AC XY: 365AN XY: 727014
GnomAD4 genome AF: 0.000650 AC: 99AN: 152364Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59AN XY: 74506
ClinVar
Submissions by phenotype
not provided Benign:5
MLH1: BP4, BP7 -
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Colorectal cancer, hereditary nonpolyposis, type 2 Benign:4
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
not specified Benign:3
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. -
DNA sequence analysis of the MUTYH gene demonstrated a sequence change, c.925C>T, in exon 10 that results in an amino acid change, p.Arg309Cys. This sequence change has been described in the gnomAD database with a frequency of 0.09% in the European population (dbSNP rs138089183). The p.Arg309Cys change affects a poorly conserved amino acid residue located in a domain of the MUTYH protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg309Cys substitution. The c.925C>T sequence change has been identified in individuals with colorectal polyps and/or colorectal cancer (PMIDs: 19732775; 19527492, 27829682). Out et al., 2012, identified the p.Arg309Cys change in individuals with a personal and/or family history of breast cancer and in controls, without a statistically significant difference in the rates of detection between the two populations (PMID: 22297469). In vitro analyses of the p.Arg309Cys change have shown contradictory results. Goto et al., 2010, demonstrated that the variant retains normal glycosylase activity in vitro (PMID: 20848659). However, Brinkmeyer et al., 2015, and Komine et al., 2015, performed in vitro assays that demonstrated significant decreases in enzyme activity, binding activity to damaged DNA, and defective base excision repair activity (PMIDs: 26377631, 25820570). Due to these contrasting evidences, the clinical significance of the p.Arg309Cys change remains unknown at this time. -
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Hereditary cancer-predisposing syndrome Benign:3
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. -
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Breast and/or ovarian cancer Benign:1
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Lynch syndrome Benign:1
Synonymous substitution with no effect on splicing, tested with NMD inhibitor -
MLH1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Malignant tumor of breast Benign:1
The MLH1 p.Ala125= variant was identified in dbSNP (ID: rs1800144 as With Likely benign allele), ClinVar (likely benign as reviewed by expert panel; 8x as benign or likely benign), Cosmic (1x), UMD-LSDB (9x, classified as neutral, co-occurred with pathogenic variants in MLH1 or MSH2 3x), Insight Colon Cancer Gene Variant Database (6x, as likely not pathogenic), and Mismatch Repair Genes Variant Database. The variant was also identified in control databases in 150 of 277158 chromosomes at a frequency of 0.0005, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was identified in the following populations: African in 4 of 24038 chromosomes (freq: 0.0002), Other in 3 of 6464 chromosomes (freq: 0.0005), Latino in 77 of 34418 chromosomes (freq: 0.002237), European Non-Finnish in 65 of 126642 chromosomes (freq: 0.0005), and Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, or South Asian populations. The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The p.Ala125= 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 silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, one study using RT-PCR from patient RNA followed by sequencing did not detect aberrant splicing (Auclair 2006). In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at