rs63750865

Variant names:

• chr3-37006991-AG-A
• rs63750865
• NM_000249.4:c.382delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.382delG​(p.Ala128GlnfsTer8) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A128A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.67

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

Our verdict: Pathogenic. The variant received 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 3-37006991-AG-A is Pathogenic according to our data. Variant chr3-37006991-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 90201.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37006991-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.382delG	p.Ala128GlnfsTer8	frameshift_variant, splice_region_variant	Exon 5 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.382delG	p.Ala128GlnfsTer8	frameshift_variant, splice_region_variant	Exon 5 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Dec 25, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 1 nucleotide from exon 5 of the MLH1 mRNA (c.382delG), causing a frameshift at codon 128. This creates a premature translational stop signal (p.Ala128Glnfs*8) and is expected to result in an absent or disrupted protein product. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in a family with individuals affected with breast cancer and with colon cancer (PMID: 17026620). For these reasons, this variant has been classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 25, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Truncating variants in MLH1 are known to be pathogenic. This particular truncation has been reported in a family with individuals affected with breast cancer and with colon cancer  (PMID: 17026620). This sequence change deletes 1 nucleotide from exon 5 of the MLH1 mRNA (c.382delG), causing a frameshift at codon 128. This creates a premature translational stop signal (p.Ala128Glnfs*8) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs63750865; hg19: chr3-37048482;