chr14-75047489-C-A

Variant names:

• chr14-75047489-C-A
• rs28756989
• NM_001040108.2:c.2167G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040108.2(MLH3):​c.2167G>T​(p.Val723Phe) 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. 16/22 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. V723I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.616
• Publications: 0 publications found

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]

MLH3 Gene-Disease associations (from GenCC):

• colorectal cancer, hereditary nonpolyposis, type 7

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17265931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2167G>T	p.Val723Phe	missense_variant	Exon 2 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.2167G>T	p.Val723Phe	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.2167G>T	p.Val723Phe	missense_variant	Exon 2 of 12	1		ENSP00000370355.3
MLH3	ENST00000556257.5	c.2167G>T	p.Val723Phe	missense_variant	Exon 2 of 7	5		ENSP00000451540.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V723F variant (also known as c.2167G>T), located in coding exon 1 of the MLH3 gene, results from a G to T substitution at nucleotide position 2167. The valine at codon 723 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated 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	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.12
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T;.;.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.69	T;T;T;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;L;.;L
PhyloP100		-0.62
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D;.;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.94	P;D;.;P
Vest4		0.26
MutPred		0.31		Gain of catalytic residue at W719 (P = 0.0022);Gain of catalytic residue at W719 (P = 0.0022);Gain of catalytic residue at W719 (P = 0.0022);Gain of catalytic residue at W719 (P = 0.0022);
MVP		0.53
MPC		0.29
ClinPred		0.46	T
GERP RS		-3.9
Varity_R		0.068
gMVP		0.34
Mutation Taster		=291/9	polymorphism

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

Other links and lift over

dbSNP: rs28756989; hg19: chr14-75514192;