chr3-37000978-TG-T

Variant names:

• chr3-37000978-TG-T
• rs587778997
• NM_000249.4:c.232delG

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.232delG​(p.Glu78LysfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E78E) 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
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.42
• Publications: 2 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37000978-TG-T is Pathogenic according to our data. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000978-TG-T is described in CliVar as Pathogenic. Clinvar id is 90114.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.232delG	p.Glu78LysfsTer14	frameshift_variant	Exon 3 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.232delG	p.Glu78LysfsTer14	frameshift_variant	Exon 3 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:4

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Jul 12, 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 frameshift 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 variation resulting in premature termination codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Mar 15, 2018

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. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 90114). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu78Lysfs*14) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 20, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232delG pathogenic mutation, located in coding exon 3 of the MLH1 gene, results from a deletion of one nucleotide at nucleotide position 232, causing a translational frameshift with a predicted alternate stop codon (p.E78Kfs*14). 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 v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -23

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

Other links and lift over

dbSNP: rs587778997; hg19: chr3-37042469;