NM_000249.4:c.1238_1239delCA

Variant names:

• chr3-37025833-TCA-T
• rs1553651073
• NM_000249.4:c.1238_1239delCA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000249.4(MLH1):​c.1238_1239delCA​(p.Thr413ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as no classifications from unflagged records (no stars). Synonymous variant affecting the same amino acid position (i.e. T413T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1 U:1
• Conservation: PhyloP100: -0.264
• Publications: 0 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 10 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

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.1238_1239delCA	p.Thr413ArgfsTer3	frameshift	Exon 12 of 19	NP_000240.1
	MLH1	NM_001354628.2		c.1238_1239delCA	p.Thr413ArgfsTer3	frameshift	Exon 12 of 18	NP_001341557.1
	MLH1	NM_001354629.2		c.1139_1140delCA	p.Thr380ArgfsTer3	frameshift	Exon 11 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.1238_1239delCA	p.Thr413ArgfsTer3	frameshift	Exon 12 of 19	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.1238_1239delCA	p.Thr413ArgfsTer3	frameshift	Exon 12 of 17	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.1238_1239delCA	p.Thr413ArgfsTer3	frameshift	Exon 12 of 15	ENSP00000416476.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no classifications from unflagged records

Submissions by phenotype

Colon cancer Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

The MLH1, c.1238_1239delCA, p.Thr412ArgfsX3 variant has not been reported in the literature nor previously identified by our laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 413 and leads to a premature stop codon, 3 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants are an established mechanism of disease for the MLH1 gene. In summary, based on the above information, this variant is classified as pathogenic.

not provided Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26
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: rs1553651073; hg19: chr3-37067324;