3-36993584-G-T

Variant names:

• chr3-36993584-G-T
• rs587779008
• NM_000249.4:c.37G>T

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.37G>T​(p.Glu13*) variant causes a stop gained change involving the alteration of a 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. E13E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH1 NM_000249.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.49
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1571 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-36993584-G-T is Pathogenic according to our data. Variant chr3-36993584-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 90189.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 19	NP_000240.1
	MLH1	NM_001354628.2		c.37G>T	p.Glu13*	stop_gained	Exon 1 of 18	NP_001341557.1
	MLH1	NM_001354629.2		c.37G>T	p.Glu13*	stop_gained	Exon 1 of 18	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 19	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 17	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.37G>T	p.Glu13*	stop_gained	Exon 1 of 15	ENSP00000416476.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000388 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Jul 07, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Lynch syndrome Pathogenic:1

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

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Apr 19, 2023

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. ClinVar contains an entry for this variant (Variation ID: 90189). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 22453149, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu13*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E13* pathogenic mutation (also known as c.37G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 37. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This pathogenic mutation has been reported in a multiple individuals with suspicion for Lynch syndrome (Brzia D et al. Exp. Oncol. 2012;34(1):49-52; Rouleau E et al. Hum. Mutat. 2009 Jun;30(6):867-75; Ikenoue T et al. J Hum Genet, 2019 Dec;64:1187-1194; Henriksson I et al. J Community Genet, 2019 Apr;10:259-266). This pathogenic mutation has also been identified in several probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MLH1 and/or PMS2 expression by immunohistochemistry (Ambry internal data; Pearlman R et al. J Med Genet, 2019 07;56:462-470). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.5
Vest4		0.85
GERP RS		6.0
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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

Other links and lift over

dbSNP: rs587779008; hg19: chr3-37035075; COSMIC: COSV105856775;