rs1057518875

Positions:

• chr14-75046622-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040108.2(MLH3):​c.3034G>A​(p.Ala1012Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. A1012V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.165

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052578688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.3034G>A	p.Ala1012Thr	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.3034G>A	p.Ala1012Thr	missense_variant	2/13	5	NM_001040108.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Breast carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 05, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.4
DANN	Benign	0.74
DEOGEN2	Benign	0.093	T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.33	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.29	T;.;T;T
Sift4G	Uncertain	0.028	D;D;T;D
Polyphen		0.0010	B;B;.;B
Vest4		0.022
MutPred		0.20		Gain of catalytic residue at T1013 (P = 0.0012);Gain of catalytic residue at T1013 (P = 0.0012);Gain of catalytic residue at T1013 (P = 0.0012);Gain of catalytic residue at T1013 (P = 0.0012);
MVP		0.61
MPC		0.096
ClinPred		0.089	T
GERP RS		-5.8
Varity_R		0.017
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057518875; hg19: chr14-75513325;