3-36993263-G-A

Variant names:

• chr3-36993263-G-A
• rs876659532
• ENST00000673673.2:c.-285G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000673673.2(MLH1):​c.-285G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 617,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: MLH1 ENST00000673673.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830
• Publications: 0 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]

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2AIP1	NM_014805.4	c.-186C>T		upstream_gene_variant		ENST00000322716.8	NP_055620.1
MLH1	XM_047448155.1	c.-824G>A		upstream_gene_variant			XP_047304111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2AIP1	ENST00000322716.8	c.-186C>T		upstream_gene_variant		6	NM_014805.4	ENSP00000406027.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000324 AC: 2 AN: 617910 Hom.: 0 Cov.: 8 AF XY: 0.00000626 AC XY: 2 AN XY: 319496

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000650 AC: 1 AN: 15394

American (AMR) AF: 0.0000510 AC: 1 AN: 19622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14810

East Asian (EAS) AF: 0.00 AC: 0 AN: 32264

South Asian (SAS) AF: 0.00 AC: 0 AN: 50110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2326

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 406934

Other (OTH) AF: 0.00 AC: 0 AN: 31374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 09, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-285G>A variant is located in the 5' untranslated region (5’ UTR) of the MLH1 gene. This variant results from a G to A substitution 285 bases upstream from the first translated codon. This nucleotide position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		0.083
PromoterAI		-0.025	Neutral

Splicing

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

Other links and lift over

dbSNP: rs876659532; hg19: chr3-37034754;