rs63751651

Positions:

• chr3-37050483-CAG-C

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.2104_2105delAG​(p.Ser702fs) variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 6.03

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37050483-CAG-C is Pathogenic according to our data. Variant chr3-37050483-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 90059.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050483-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2104_2105delAG	p.Ser702fs	frameshift_variant, splice_region_variant	19/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2104_2105delAG	p.Ser702fs	frameshift_variant, splice_region_variant	19/19	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:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:1 Uncertain:1

Pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	Coding sequence variation resulting in a stop codon -
Uncertain significance, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	May 01, 2018	MLH1 NM_000249.3:c.2104-1_2104-2del has a 93.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2019

The c.2104_2105delAG variant, located in coding exon 19 of the MLH1 gene, results from a deletion of two nucleotides at nucleotide positions 2104 to 2105, leading to an alternate stop codon (p.S702*). This variant has been reported in an individual diagnosed with MSI-high colorectal cancer meeting Amsterdam I criteria; MLH1 and MSH2 proteins were reported as present by immunohistochemistry (IHC) (Syngal S et al. JAMA, 1999 Jul;282:247-53; Wahlberg SS et al. Cancer Res., 2002 Jun;62:3485-92). This truncation occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 55 amino acids of the protein. However, structural analysis suggests that this alteration perturbs a known functional domain responsible for binding to and stabilizing PMS2 (Mohd AB et al. DNA Repair (Amst.), 2006 Mar;5:347-61). As such, this alteration is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.77		Position offset: 5
DS_AL_spliceai		0.93		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751651; hg19: chr3-37091974;