chr3-37050534-C-T
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1
The NM_000249.4(MLH1):c.2152C>T(p.His718Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,142 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H718P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0217 AC: 3306AN: 152196Hom.: 113 Cov.: 33
GnomAD3 exomes AF: 0.00563 AC: 1415AN: 251118Hom.: 59 AF XY: 0.00410 AC XY: 557AN XY: 135700
GnomAD4 exome AF: 0.00219 AC: 3208AN: 1461828Hom.: 107 Cov.: 31 AF XY: 0.00191 AC XY: 1391AN XY: 727216
GnomAD4 genome AF: 0.0217 AC: 3310AN: 152314Hom.: 115 Cov.: 33 AF XY: 0.0207 AC XY: 1543AN XY: 74482
ClinVar
Submissions by phenotype
not specified Benign:9Other:1
The His718Tyr variant (rs2020873) in MLH1 is present in various populations at f requencies ranging from ~1% to ~16% and is more common individuals with African ancestry. In addition, this variant was reported in patient and control chromoso mes with equal frequncy (Barnetson 2008, Moussa 2011, Weber 1999). Finally, func tional studies have shown the His718Tyr has no discernbile impact on the functio n of the MMR complex (Martinez 2010, Kondo 2003). Therefore this variant is beni gn and not expected to have clinical significance. -
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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. -
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Hereditary cancer-predisposing syndrome Benign:5
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This alteration is classified as 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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Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:3
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. -
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Lynch syndrome Benign:4
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MAF >1% -
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not provided Benign:4
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MLH1: PM5, BS1, BS2 -
Carcinoma of colon Benign:1
The MLH1 p.His718Tyr variant was identified in 6 of 2626 proband chromosomes (frequency: 0.002) from individuals with sporadic colorectal cancer or suspected HNPCC, none of whom met complete requirements of the Amsterdam or Bethesda criteria (Kim 2004, Kondo 2003, Takahashi 2007, Moussa 2011, Schafmayer 2007). This variant was also identified in 17 of 2254 control chromosomes from the above studies (frequency: 0.008), in the 1000 Genomes Project with a frequency of 0.028, and in the Exome Variant Server ESP Project with a frequency of 0.07 amongst African American alleles, suggesting that this variant may represent a benign polymorphism in certain populations. The variant was also reported in dbSNP (rs2020873) and LOVD. In vitro MMR assays and yeast hybrid-two assays examining the ability of the variant to repair a heteroduplex DNA with mismatch bases found that its activity was similar to that of wildtype (Kondo 2003, Takahashi 2007), suggesting that this is a nonpathogenic alteration. The p.His718 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.His718Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, we cannot determine the clinical significance of this variant with certainty at this time, although we would lean towards a more benign role for this variant. In summary, this variant is classified as predicted benign. -
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