Genetic Variant ENST00000673673.2:c.-320G>C (chr3-36993228-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000673673.2(MLH1):c.-320G>C variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000126 in 795,424 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: 0.0000013 ( 0 hom. )

Consequence

MLH1
ENST00000673673.2 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

Publications

0 publications found

Variant links:

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 links:

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]

EPM2AIP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2AIP1	NM_014805.4 link	c.-151C>G		upstream_gene_variant		ENST00000322716.8	NP_055620.1	Q7L775
MLH1	XM_047448155.1 link	c.-859G>C		upstream_gene_variant			XP_047304111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPM2AIP1	ENST00000322716.8 link	c.-151C>G		upstream_gene_variant		6	NM_014805.4	ENSP00000406027.1		Q7L775

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000126

AC:

AN:

795424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

406362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18982

American (AMR)

AF:

0.00

AC:

AN:

23286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16056

East Asian (EAS)

AF:

0.00

AC:

AN:

35186

South Asian (SAS)

AF:

0.00

AC:

AN:

56100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2804

European-Non Finnish (NFE)

AF:

0.00000179

AC:

AN:

558280

Other (OTH)

AF:

0.00

AC:

AN:

37418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Jul 15, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-320G>C variant is located in the 5' untranslated region (5’ UTR) of the MLH1 gene. This variant results from a G to C substitution 320 bases upstream from the first translated codon. This nucleotide position is highly 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

-0.42

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

4.0

PromoterAI

-0.099

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over