3-37050490-A-G

Position:

• chr3-37050490-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The ENST00000450420.6(MLH1):​c.1563A>G​(p.Ter521Trpext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. *521*) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 ENST00000450420.6 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000450420.6 Downstream stopcodon found after 530 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2108A>G	p.Glu703Gly	missense_variant	19/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2108A>G	p.Glu703Gly	missense_variant	19/19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The p.E703G variant (also known as c.2108A>G), located in coding exon 19 of the MLH1 gene, results from an A to G substitution at nucleotide position 2108. The glutamic acid at codon 703 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Uncertain	0.77	D;.;.;.;.;.
Eigen	Benign	0.038
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.62	T;T;.;.;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D;.;D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.14	T;.;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.
Vest4		0.13
MutPred		0.19		Gain of glycosylation at S702 (P = 0.0483);.;.;.;.;.;
MVP		0.92
MPC		0.077
ClinPred		0.30	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-37091981;