rs1553648149

Positions:

• chr3-37020418-GAGCA-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.997_1000delAAGC​(p.Lys333fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.76

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]

MLH1 (HGNC:):

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 3-37020418-GAGCA-G is Pathogenic according to our data. Variant chr3-37020418-GAGCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 483540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37020418-GAGCA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.997_1000delAAGC	p.Lys333fs	frameshift_variant	11/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.997_1000delAAGC	p.Lys333fs	frameshift_variant	11/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 02, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2015	This deletion of 4 nucleotides in MLH1 is denoted c.997_1000delAAGC at the cDNA level and p.Lys333SerfsX33 (K333SfsX33) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GAGC[delAAGC]TCCT. The deletion causes a frameshift, which changes a Lysine to a Serine at codon 333, and creates a premature stop codon at position 33 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MLH1 c.997_1000delAAGC has been reported in at least one individual with a history of Lynch syndrome (Casey 2005). we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2015	The c.997_1000delAAGC pathogenic mutation (also known as c.997del4), located in coding exon 11 of the MLH1 gene, results from a deletion of 4 nucleotides between nucleotide positions 997 and 1000, causing a translational frameshift with a predicted alternate stop codon. This mutation was seen once in a cohort of 89 colorectal cancer patients determined to have a high probability of carrying a mismatch repair germline mutation. The individual carrying this mutation was found to have loss of MLH1 on immunohistochemistry analysis (IHC), and the mutation was determined to be deleterious at the mRNA level by conversion analysis performed on lymphoblastoid cell lines (Casey G et al. JAMA 2005; 293(7):799-809). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008; 10:294). -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 29, 2020	This variant deletes 4 nucleotides in exon 11 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch Syndrome (PMID: 15713769, 28874130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 18, 2023

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has been observed in individuals affected with Lynch syndrome (PMID: 15713769, 28874130). ClinVar contains an entry for this variant (Variation ID: 483540). This sequence change creates a premature translational stop signal (p.Lys333Serfs*33) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. -

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: rs1553648149; hg19: chr3-37061909;