rs63750978

chr3-37050524-G-Achr3-37050524-G-Cchr3-37050524-G-T

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.2142G>A(p.Trp714Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 9.76

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]

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 68 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37050524-G-A is Pathogenic according to our data. Variant chr3-37050524-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 418308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.2142G>A	p.Trp714Ter	stop_gained	19/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.2142G>A	p.Trp714Ter	stop_gained	19/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 43 amino acids are lost, and other loss-of-function variants have been reported downstream in Clinvar (Landrum 2014); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 21901500, 8880570, 11093816, 27601186, 9833759, 25345868, 19931546, 15322516, 17510385, 9697702, 28514183, 28466842, 29238914, 25110875, 31447099) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 12, 2022	This nonsense variant causes the premature termination of MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been observed in individuals with Lynch syndrome or a Lynch Syndrome associated phenotype (PMID: 8880570 (1996), PMID: 31447099 (2019), PMID: 29238914 (2018), PMID: 21901500 (2012), PMID: 15731775 (2005)). Based on the available information, this variant is classified as pathogenic. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 25, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 28, 2021	This variant changes 1 nucleotide in exon 19 of the MLH1 gene, creating a premature translation stop signal in the last coding exon. Although functional studies have not been reported, this variant is expected to disrupt the PMS2/MLH3/PMS1 interacting domain (PMID: 12799449, 16338176, 20533529). This variant has been reported in individuals affected with Lynch syndrome (PMID: 8880570, 25345868; DOI: 10.3343/lmo.2018.8.4.156; Salehi 2008). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2024	The p.W714* pathogenic mutation (also known as c.2142G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2142. This changes the amino acid from a tryptophan to a stop codon within coding exon 19. This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been seen in an English HNPCC family containing multiple family members with colorectal cancer (Froggatt NJ et al. J. Med. Genet. 1996 Sep;33:726-30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 23, 2016

Variant summary: The MLH1 c.2142G>A (p.Trp714X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2179_2182delCACA (p.His727fsX55) and c.2252_2253delAA (p.Lys751fsX3). Multiple publications cite the variant in affected individuals, along with a reputable database classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2023

This sequence change creates a premature translational stop signal (p.Trp714*) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 8880570). This variant is also known as 2163G>A. ClinVar contains an entry for this variant (Variation ID: 418308). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys732*) have been determined to be pathogenic (PMID: 10422993, 10923051, 12799449, 16338176, 20533529, 25197397; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	41
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.28	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
MVP		0.97
ClinPred		0.93	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63750978; hg19: chr3-37092015;