rs63749875

Positions:

• chr3-37050552-T-A
• chr3-37050552-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PS1_Moderate PM2 BP6

The NM_000249.4(MLH1):​c.2170T>A​(p.Leu724Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36

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 Uncertain_significance. Variant got 3 ACMG points.

• PS1: Transcript NM_000249.4 (MLH1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 3-37050552-T-A is Benign according to our data. Variant chr3-37050552-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH1	NM_000249.4	c.2170T>A	p.Leu724Met	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.2170T>A	p.Leu724Met	missense_variant	19/19	1	NM_000249.4	ENSP00000231790	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T;.;.;.;T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.73	N;.;.;.;.;.
MutationTaster	Benign	0.54	D;D;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.13	N;.;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T;.;D;D;D;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.26
MutPred		0.80		Loss of catalytic residue at L724 (P = 0.0331);.;.;.;.;.;
MVP		0.98
MPC		0.073
ClinPred		0.71	D
GERP RS		4.3
Varity_R		0.29
gMVP		0.54

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: rs63749875; hg19: chr3-37092043;