chr3-37025833-TCA-T

Position:

• chr3-37025833-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000249.4(MLH1):​c.1238_1239delCA​(p.Thr413fs) 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). 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

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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
• PP5: Variant 3-37025833-TCA-T is Pathogenic according to our data. Variant chr3-37025833-TCA-T is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 433865.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1238_1239delCA	p.Thr413fs	frameshift_variant	12/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1238_1239delCA	p.Thr413fs	frameshift_variant	12/19	1	NM_000249.4	ENSP00000231790.3

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

Pathogenic, flagged submission

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, flagged submission

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

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: rs1553651073; hg19: chr3-37067324;