rs63751688

chr3-37040188-C-Achr3-37040188-C-Gchr3-37040188-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000249.4(MLH1):c.1561C>A(p.Leu521Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L521F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000249.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1561C>A	p.Leu521Ile	missense_variant, splice_region_variant	14/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1561C>A	p.Leu521Ile	missense_variant, splice_region_variant	14/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 13, 2022

The c.1561C>A (p.L521I) alteration is located in exon 14 (coding exon 14) of the MLH1 gene. This alteration results from a C to A substitution at nucleotide position 1561, causing the leucine (L) at amino acid position 521 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.;.;.;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;.;.;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;.
Vest4		0.46
MutPred		0.36		Loss of sheet (P = 0.0357);.;.;.;.;.;.;
MVP		0.82
MPC		0.40
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.75
gMVP		0.48

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: rs63751688; hg19: chr3-37081679; COSMIC: COSV51615753;