rs63750447
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_000249.4(MLH1):c.1151T>A(p.Val384Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,706 control chromosomes in the GnomAD database, including 21 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 -19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00105 AC: 160AN: 151706Hom.: 2 Cov.: 31
GnomAD3 exomes AF: 0.00271 AC: 682AN: 251422Hom.: 7 AF XY: 0.00259 AC XY: 352AN XY: 135876
GnomAD4 exome AF: 0.00101 AC: 1471AN: 1461884Hom.: 19 Cov.: 34 AF XY: 0.000954 AC XY: 694AN XY: 727244
GnomAD4 genome AF: 0.00105 AC: 160AN: 151822Hom.: 2 Cov.: 31 AF XY: 0.00113 AC XY: 84AN XY: 74180
ClinVar
Submissions by phenotype
not specified Benign:8Other:1
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Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.9% East Asian chromosomes -
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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. -
Colorectal cancer, hereditary nonpolyposis, type 2 Benign:3
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not provided Benign:3
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MLH1: BS1, BS2 -
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Hereditary cancer-predisposing syndrome Benign:3
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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. -
Breast and/or ovarian cancer Benign:1
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Lynch syndrome 1 Benign:1
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Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Benign:1
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Lynch syndrome Benign:1
MAF >1% -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Bile duct cancer Benign:1
The MLH1 p.Val384Asp variant was identified in the literature and by our laboratory. It was identified in 104 of 3286 proband chromosomes (allele frequency 0.03) with different cancer types including colon, pancreatic and lung; and was identified in 53 of 2818 race-matched control chromosomes (allele frequency 0.03), increasing the likelihood that this is a benign variant in certain populations of origin (Chao 2008, Fan 2007, Kim 2010, Kim 2004, Ku 2002, Li 2005 , Lee 2005, Mei 2006, Ohsawa 2009, Shi 2003, Wang 2007, Wang 1998, Yan 2008 , Yap 2009, Yuan 2004,). The variant was also identified in dbSNP (ID: rs63750447) with a minor allele frequency of 0.009 (1000 Genomes Project), COSMIC, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, ClinVar database, and UMD (2X as a neutral variant). The variant was identified in co-occurrence with pathogenic MLH1 variants by Lee (2005) (c.1459C > T (p.Arg487X)), by our laboratory (c.453+1G>T, r.spl?), and in a sample submitted to UMD (c.453+1G>T), increasing the likelihood that the p.Val384Asp variant does not have clinical importance. In addition, based on a personal communication with the Pathology Department of the University of Hong Kong, sequencing on normal population DNA from their locality (108 normal blood DNA), this variant was found in 7 individuals and was regarded as a non-pathogenic variant. Furthermore, the variant was classified as benign by 4 submitters to the ClinVar database: InSiGHT (reviewed by expert panel), GeneDX, Ambry Genetics, and the Biesecker Laboratory – ClinSeq Project. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at