rs1553664506

chr3-37048960-GTTC-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM4_Supporting PP5_Moderate

The NM_000249.4(MLH1):c.2048_2050del(p.Phe683del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F683F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.44

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000249.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000249.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-37048960-GTTC-G is Pathogenic according to our data. Variant chr3-37048960-GTTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433872.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.2048_2050del	p.Phe683del	inframe_deletion	18/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.2048_2050del	p.Phe683del	inframe_deletion	18/19	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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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Review this variant with Melyssa Aronson before sign out - Delegate to JLE -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2017

The c.2048_2050delTCT variant (also known as p.F683del) is located in coding exon 18 of the MLH1 gene. This variant results from an in-frame TCT deletion at nucleotide positions 2048 to 2050. This results in the in-frame deletion of a phenylalanine at codon 683. This alteration showed moderate segregation with disease in a family that met Amsterdam II criteria and two family members who tested positive for this alteration also displayed loss of MLH1 protein expression in their tumors by immunohistochemistry (Ambry internal data). Based on internal structural analysis, this alteration is part of a structured region with known function and is more destabilizing than known likely pathogenic variants in the region. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al., Bioinformatics 2015 Aug; 31(16):2745-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553664506; hg19: chr3-37090451;