3-37047639-AA-GC
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM2PM5BP6_Very_Strong
The NM_000249.4(MLH1):c.1852_1853delAAinsGC(p.Lys618Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K618E) has been classified as Likely benign.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:7Other:1
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Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:2Benign:2
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Hereditary cancer-predisposing syndrome Uncertain:1Benign: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. -
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not provided Benign:4
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MLH1: BS1, BS2 -
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Lynch syndrome Benign:2
Multifactorial likelihood analysis posterior probability <0.001 -
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Breast and/or ovarian cancer Benign:1
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Carcinoma of colon Benign:1
The p.Lys618Ala variant has been previously reported in the literature. It has been identified in 48/8212 (Freq: 0.006) proband chromosomes from families with colorectal cancer and or other cancer types and in 29/6204 (Freq: 0.005) control chromosomes, increasing the likelihood that this is a polymorphism (Auclair_2006_16395668; Barnetson_2008_18033691; Belvederesi_2006_16724012; Bianchi_2007_17250665; Fearnhead_2004_15520370; Fidalgo_2000_10713887; Gille_2002_12373605; Hampel_2006_16885385; Hedge_2005_16237223; Hudler_2004_15099349; Papp_2007_17569143; Perera_2007_18205192; Pinol_2005_15855432; Rubio-Del-Campo_2007_18325052; Scott_2001_11112663; Steinke_2008_18301448; Syngal_1999_10422993; Ward_2002_12200596; Weber_1997_9288790; Wolf_200515926618; Wijnen_1997_9311737; Tannergard_1995_8521398). Contradictory evidence exists regarding the functional significance of this variant. In vitro studies have demonstrated that the p.Lys618Ala substitution results in an 85% reduction in efficiency of binding to PMS2 and that it was unable to reverse the mutator phenotype in an MLH1 deficient ovarian cancer cell line (Blasi_2006_16982745; Guerrette_1999_10037723). However, Perera et al (2007) demonstrated that the p.Lys618Ala variant did not appear to perturb the ability of MLH1 to heterodimerize with the PMS2 protein. Although, they also showed that the variant protein had a half-life that was significantly decreased compared to the wild-type protein (Perera_2007_18205192), suggesting that this variant may have some functional consequence. There is a significant evidence against the pathogenicity of this variant. Previous studies have identified p.Lys618Ala variant in patients with Microsatelite Stable colorectal carcinomas that expressed MLH1 (Farrington et al., 1998; Liu_1999_10598809; Mauillon et al., 1996; Muller-Koch_2001_11726306; Samowitz et al., 2001; Wolf_2005_15926618). Several studies report this variant in the presence of a second variant which was in some cases pathogenic. For example an out-of-frame splice mutation (a A>G at position –2 in intron 6 of the hMLH1-gene). The splice mutation caused skipping of exon 7 and was shared with a younger sibling who had three consecutive CRCs and gastric cancer, all associated with MSI (Liu_1999_10598809). In this case, the p.Lys618Ala variant did not co-segregate with disease (Tannergard_1995_8521398). Still in another study, the MSH2 protein product was demonstrated to be absent and the MLH1 protein product was present in one affected individual with this variant, increasing the likelihood that the p.Lys618Ala variant is not pathogenic (Pinol_2005_15855432). Steinke et al (2008_18301448) also identified this variant in the presence of a second variant in two individuals, one was a pathogenic stop codon (Syngal_1999_10422993). In summary, based on the above information, this variant is predicted to be benign. Although it is predicted benign we cannot rule out that it may contribute to or modify the clinical features observed in this individual. -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 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