3-37020402-T-C
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4BP6_Very_StrongBS1BS2
The NM_000249.4(MLH1):c.977T>C(p.Val326Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000579 in 1,614,136 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Consequence
NM_000249.4 missense
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: 0.000440 AC: 67AN: 152138Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.000469 AC: 118AN: 251388Hom.: 1 AF XY: 0.000611 AC XY: 83AN XY: 135862
GnomAD4 exome AF: 0.000594 AC: 868AN: 1461880Hom.: 2 Cov.: 31 AF XY: 0.000671 AC XY: 488AN XY: 727246
GnomAD4 genome AF: 0.000433 AC: 66AN: 152256Hom.: 2 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74448
ClinVar
Submissions by phenotype
not specified Benign:8Other:1
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proposed classification - variant undergoing re-assessment, contact laboratory -
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Variant summary: The variant, MLH1 c.977T>C (p.Val326Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 278288 control chromosomes, predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. This variant was found in two affected members from a Lynch family (example, Hardt 2011). Detailed genotypic and phenotypic information was not available to assert whether or not the variant co-segregated with disease. In contrast, in one family, this variant did not co-segregate with the disease: while one affected member was positive for the variant, other two affected members did not carry the variant (Pastrello 2011). In addition, tumor tissues from patients with this variant showed no loss of heterozygosity, normal expression of MLH1 or MSH2, and normal microsatellite instability (Dieumegard 2000, Spaepen 2006, Pastrello 2011, Hardt 2011). In vitro MMR and dominant mutator effect studies showed conflicting results (Shimodaira 1998, Trojan 2002, Takahashi 2007) although supporting a functional MMR activity (Trojan_2002). Furthermore, a yeast two-hybrid assay showed that hMLH1 V326A can interact with hPMS2 and hEXO1 (Kondo 2003) and the variant was shown to not affect normal splicing (Borras 2012). Twelve clinical diagnostic laboratories and one expert panel (INSIGHT) have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. Eleven of them, to include the expert panel have classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:6
MLH1: BS1 -
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This variant is associated with the following publications: (PMID: 8574961, 22949387, 9697702, 20176959, 18561205, 10573010, 16736289, 8592341, 16885385, 10446963, 9506527, 10448273, 17594722, 24728327, 23588873, 25637381, 22736432, 24055113, 25871441, 10732761, 21239990, 12810663, 17510385, 21404117, 11781295, 11555625, 17192056, 22290698, 15340264, 10601588, 26976419, 24362816, 20533529, 30998989) -
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Hereditary cancer-predisposing syndrome Benign:5
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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Lynch syndrome Uncertain:1Benign:2
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Multifactorial likelihood analysis posterior probability <0.001 -
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Colorectal cancer, hereditary nonpolyposis, type 2 Benign:2
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Colorectal cancer, non-polyposis Uncertain:1
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Breast and/or ovarian cancer Benign:1
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Lynch syndrome 1 Benign:1
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Muir-Torré syndrome 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