rs63751653
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.588delA(p.Lys196AsnfsTer6) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000249.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251370Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135862
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460778Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726806
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Lynch-like syndrome Pathogenic:1
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Lynch syndrome Pathogenic:1
Coding sequence variation resulting in a stop codon -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Lys196Asnfs*6) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is present in population databases (rs35847123, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 21642682, 25117503). ClinVar contains an entry for this variant (Variation ID: 90287). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.588delA pathogenic mutation, located in coding exon 7 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 588, causing a translational frameshift with a predicted alternate stop codon (p.K196Nfs*6). In addition, this deletion of the last base pair of coding exon 7 is likely to have some effect on normal mRNA splicing. This mutation has been reported in multiple unrelated French families diagnosed with HNPCC/Lynch syndrome, and it was presumed to be disruptive to the native splice site; however, experimental evidence for abnormal splicing was not available (Parc Y et al. J. Med. Genet. 2003 Mar;40(3):208-13; Bonadona V et al. JAMA. 2011 Jun 8;305(22):2304-10). This alteration has also been reported in conjunction with a monoallelic MUTYH mutation in an individual with colorectal and prostate cancers, which both displayed lack of MLH1 and PMS2 protein expression by IHC (Rosty C et al. Fam. Cancer 2014 Dec;13(4):573-82; Win AK et al. Fam. Cancer 2015 Dec;14(4):575-83). In addition to being identified as germline in individuals meeting Amsterdam criteria, this mutation has been identified to be of somatic origin in conjunction with second MLH1 pathogenic mutations in multiple Lynch syndrome-related tumors (Sourrouille I et al. Fam. Cancer, 2013 Mar;12:27-33; Haraldsdottir S et al. Nat Commun, 2017 05;8:14755; Golubicki M et al. Cancers (Basel), 2021 Mar;13; Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation, aberrant splicing, or nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at