rs587778930

chr3-37040213-CCTT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM4_Supporting PP5_Very_Strong

The NM_000249.4(MLH1):c.1588_1590del(p.Phe530del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S529S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.81

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000249.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-37040213-CCTT-C is Pathogenic according to our data. Variant chr3-37040213-CCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 89798.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37040213-CCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1588_1590del	p.Phe530del	inframe_deletion	14/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1588_1590del	p.Phe530del	inframe_deletion	14/19	1	NM_000249.4	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:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 22, 2023

- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2014

The c.1588_1590delTTC variant (also known as p.F530del) is located in coding exon 14 of the MLH1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1588 to 1590 and causes the removal of a highly-conserved phenylalanine residue at codon 1530. This alteration has been described as a pathogenic mutation in Chinese family satisfying Amsterdam criteria for HNPCC/Lynch syndrome (Luo D et al. World J Gastroenterol. 2005 Mar 21;11(11):1673-9). The c.1588_1590delTTC alteration was detected in three family members diagnosed with early-onset CRC (proband and two sons) and was associated with microsatellite instability, but normal MLH1 staining in tumor tissues. This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 13000 alleles tested) in our clinical cohort (includes this individual). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 06, 2020

Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant has been observed in individual(s) with an increased risk for, or a diagnosis of Lynch syndrome (PMID: 15786548, 28514183). ClinVar contains an entry for this variant (Variation ID: 89798). This variant is not present in population databases (ExAC no frequency). This variant, c.1588_1590del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Phe530del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587778930; hg19: chr3-37081704;