3-37025979-A-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.1381A>T(p.Lys461Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K461K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 0.187

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 3-37025979-A-T is Pathogenic according to our data. Variant chr3-37025979-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 36540.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37025979-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1381A>T	p.Lys461Ter	stop_gained	12/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1381A>T	p.Lys461Ter	stop_gained	12/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 20, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 11585727]. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 20, 2023	The MLH1 c.1381A>T (p.Lys461Ter) change is a nonsense variant that is predicted to cause premature protein truncation or absence of protein due to nonsense-mediated decay. This variant has also been shown to cause exon 12 skipping in some transcripts (PMID: 11585727, 15173238). This alteration has been reported in several individuals with Lynch syndrome (PMID: 29238914, 19690142, 10422993, 30877237, 12658575, 11208710). It has also been identified in an individual diagnosed with glioblastoma whose tumor has a ultra-hypermutator phenotype (internal data). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Syngal 1999, Stella 2001, Terdiman 2001, Mueller 2009); Published functional studies demonstrate a partial splicing defect, with skipping of exon 12 in some transcripts (Stella 2001, Lastella 2004); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15173238, 12658575, 25345868, 19690142, 11585727, 25525159, 11208710, 22658618, 21155023, 30322717, 9377556, 10422993, 19931546, 27978560, 29238914, 30019097, 28944238, 28449805, 32040686, 31447099) -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2021	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. The variant was found in at least one symptomatic patient, and not found in general population data. In the literature, the variant has been reported in multiple LS and CRC pts that were MMR deficient. Experiments have shown that this variant results in partial splicing defect resulting in exon 12 skipping in some of the transcripts which was reported in LS families. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 18, 2023	This variant changes 1 nucleotide in exon 12 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancer (PMID: 19690142, 27978560, 28449805, 29238914, 30322717). RNA studies have shown this variant results in partial exon skipping of exon 12 (PMID: 11585727, 15173238). 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	Dec 13, 2021	The p.K461* pathogenic mutation (also known as c.1381A>T), located in coding exon 12 of the MLH1 gene, results from an A to T substitution at nucleotide position 1381. This changes the amino acid from a lysine to a stop codon within coding exon 12. This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families and has been shown to disrupt normal mRNA processing (Kitaeva MN et al. Cancer Res., 1997 Oct;57:4478-81; Syngal S et al. JAMA, 1999 Jul;282:247-53; Terdiman JP et al. Gastroenterology, 2001 Jan;120:21-30; Stella A et al. Cancer Res., 2001 Oct;61:7020-4; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96; Ambry internal data). 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. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change creates a premature translational stop signal (p.Lys461*) in the MLH1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. 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: 9377556, 10422993, 11208710, 11585727, 12658575, 19690142). ClinVar contains an entry for this variant (Variation ID: 36540). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (PMID: 11585727, 15173238; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Lynch syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	33
Dann	Benign	0.96
Eigen	Benign	0.12
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.89
ClinPred		0.95	D
GERP RS		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 28

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

Publications

LitVar

Other links and lift over

dbSNP: rs63750540; hg19: chr3-37067470;