rs138006166

Positions:

• chr14-75018891-C-A
• chr14-75018891-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001040108.2(MLH3):​c.4180G>T​(p.Ala1394Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1394T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-75018891-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.4180G>T	p.Ala1394Ser	missense_variant	12/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.4180G>T	p.Ala1394Ser	missense_variant	12/13	5	NM_001040108.2	ENSP00000348020	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;.;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;.
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.2	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N;.;D;N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.76
MutPred		0.67		Gain of catalytic residue at H1395 (P = 0.0028);.;.;Gain of catalytic residue at H1395 (P = 0.0028);
MVP		0.90
MPC		0.49
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.52

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: chr14-75485594;