rs281864938

chr3-37048561-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):c.1946del(p.Pro649LeufsTer12) variant causes a frameshift 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. P648P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.59

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37048561-GC-G is Pathogenic according to our data. Variant chr3-37048561-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 89954.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37048561-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1946del	p.Pro649LeufsTer12	frameshift_variant	17/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1946del	p.Pro649LeufsTer12	frameshift_variant	17/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 24, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 89954). This premature translational stop signal has been observed in individuals with Lynch syndrome with high tumor microsatellite instability (PMID: 10521294, 11291077, 14645426, 16116158, 19224586, 20215533). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro649Leufs*12) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.1946delC pathogenic mutation, located in coding exon 17 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 1946, causing a translational frameshift with a predicted alternate stop codon (p.P649Lfs*12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was identified in conjunction with a MSH6 missense alteration in a proband with MSI-H endometrial cancer (Wu Y et al. Am. J. Hum. Genet. 1999 Nov;65:1291-8) and has since been reported in individuals meeting Amsterdam criteria with MSI-H tumors and/or absent MLH1 staining by IHC analysis (Berends MJ et al. J. Clin. Oncol. 2003 Dec;21:4364-70; Niessen RC et al. Gut 2006 Dec;55:1781-8; Yap HL et al. Fam. Cancer, 2009 Aug;8:85-94). Additionally, this mutation was seen in a male breast cancer patient whose breast tumor demonstrated loss of MLH1 and PMS2 protein expression by IHC (Walsh MD et al. Clin. Cancer Res. 2010 Apr;16:2214-24). Of note, this alteration is also designated as p.P649fs and Pro649fsX661 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281864938; hg19: chr3-37090052;