3-36993571-T-G

Variant names:

• chr3-36993571-T-G
• rs748406142
• NM_000249.4:c.24T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001167617.3(MLH1):​c.-493T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLH1 NM_001167617.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.127

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.24T>G	p.Ile8Met	missense_variant	Exon 1 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.24T>G	p.Ile8Met	missense_variant	Exon 1 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jul 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 856302). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 8 of the MLH1 protein (p.Ile8Met). -

Hereditary cancer-predisposing syndrome Uncertain:1

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I8M variant (also known as c.24T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 24. The isoleucine at codon 8 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	0.043
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.77		Gain of disorder (P = 0.0474);
MVP		0.95
MPC		0.34
ClinPred		1.0	D
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.77

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: rs748406142; hg19: chr3-37035062;