rs63751592

Positions:

• chr3-37028781-CAGAA-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The ENST00000231790.8(MLH1):​c.1411_1414del​(p.Lys471AspfsTer19) variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 ENST00000231790.8 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.70

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 13 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06516953 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: cttccttttcttcattgcAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
• PP5: Variant 3-37028781-CAGAA-C is Pathogenic according to our data. Variant chr3-37028781-CAGAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 89727.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37028781-CAGAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1411_1414del	p.Lys471AspfsTer19	splice_acceptor_variant, coding_sequence_variant	13/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1411_1414del	p.Lys471AspfsTer19	splice_acceptor_variant, coding_sequence_variant	13/19	1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 20, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 14, 2020

Variant summary: MLH1 c.1411_1414delAAGA (p.Lys471AspfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251436 control chromosomes (gnomAD). c.1411_1414delAAGA has been reported in the literature in individuals affected with Lynch Syndrome (example: Hansen_2014, Liu_1996, Yurgelun_2017, Goldberg_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) and an expert panel (InSiGHT) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome Pathogenic:1

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:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 08, 2022

Frameshift 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 (Liu et al., 1996; Papp et al., 2007; Sjursen et al., 2010; Goldberg et al., 2014; Yurgelun et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 20587412, 8574961, 25430799, 24689082, 23990280, 18389388, 15926618, 30787465, 28135145, 17569143) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change creates a premature translational stop signal (p.Lys471Aspfs*19) 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). 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: 8574961, 15926618, 17569143, 18389388, 20587412). This variant is also known as c.1410_1413delAAAG. ClinVar contains an entry for this variant (Variation ID: 89727). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2022

The c.1411_1414delAAGA pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a deletion of 4 nucleotides between positions 1411 and 1414, causing a translational frameshift with a predicted alternate stop codon (p.K471Dfs*19). This well described mutation has been identified in multiple Lynch and suspected-Lynch kindreds (Liu B et al. Nat. Med. Feb 1996:2(2);169-174; Papp J et al. World J. Gastroenterol. 2007 May 21;13(19):2727-32; Goldberg Y et al. Fam Cancer. 2008 Apr;7(4):309-17; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Goldberg Y et al. Fam. Cancer 2014 Mar;13(1):65-73; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). 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 v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 7
DS_AL_spliceai		1.0		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751592; hg19: chr3-37070272;