NM_000249.4:c.2228T>C

Variant names:

• chr3-37050610-T-C
• NM_000249.4:c.2228T>C

Variant summary

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

The NM_000249.4(MLH1):​c.2228T>C​(p.Leu743Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81

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, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2228T>C	p.Leu743Pro	missense_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2228T>C	p.Leu743Pro	missense_variant	Exon 19 of 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

May 03, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L743P variant (also known as c.2228T>C), located in coding exon 19 of the MLH1 gene, results from a T to C substitution at nucleotide position 2228. The leucine at codon 743 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). 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	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;.;.;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;.;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.85
MutPred		0.89		Gain of disorder (P = 0.0504);.;.;.;.;.;
MVP		0.98
MPC		0.48
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-37092101;