chr3-37028857-A-AC

Variant names:

• chr3-37028857-A-AC
• rs63750855
• NM_000249.4:c.1489dupC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.1489dupC​(p.Arg497ProfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV004841021: In vitro yeast two-hybrid assay demonstrated that the predicted truncated protein failed to interact with PMS2 protein (PMID:?12810663)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R497R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20 O:1
• Conservation: PhyloP100: 0.659
• Publications: 19 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: ClinGen, Orphanet, G2P
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, 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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004841021: In vitro yeast two-hybrid assay demonstrated that the predicted truncated protein failed to interact with PMS2 protein (PMID:?12810663).; SCV001360798: Experimental evidence evaluating an impact on protein function demonstrated that there was no interaction between the predicted truncated protein and PMS2 (Kondo_2003).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37028857-A-AC is Pathogenic according to our data. Variant chr3-37028857-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 89753.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.1489dupC	p.Arg497ProfsTer6	frameshift	Exon 13 of 19	NP_000240.1	P40692-1
	MLH1	NM_001354628.2		c.1489dupC	p.Arg497ProfsTer6	frameshift	Exon 13 of 18	NP_001341557.1	A0A087WX20
	MLH1	NM_001354629.2		c.1390dupC	p.Arg464ProfsTer6	frameshift	Exon 12 of 18	NP_001341558.1	A0AAQ5BGZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.1489dupC	p.Arg497ProfsTer6	frameshift	Exon 13 of 19	ENSP00000231790.3	P40692-1
	MLH1	ENST00000456676.7	TSL:1	c.1489dupC	p.Arg497ProfsTer6	frameshift	Exon 13 of 17	ENSP00000416687.3	H0Y818
	MLH1	ENST00000413740.2	TSL:1	c.1489dupC	p.Arg497ProfsTer6	frameshift	Exon 13 of 15	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	not provided (9)
3	-	-	Colorectal cancer, hereditary nonpolyposis, type 2 (3)
3	-	-	Lynch syndrome (3)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	-	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
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: rs63750855; hg19: chr3-37070348; COSMIC: COSV51614362; COSMIC: COSV51614362;