rs28756980

Positions:

• chr14-75048990-C-A
• chr14-75048990-C-G
• chr14-75048990-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001040108.2(MLH3):​c.666G>T​(p.Lys222Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. K222K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.967

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.666G>T	p.Lys222Asn	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.666G>T	p.Lys222Asn	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.666G>T	p.Lys222Asn	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.666G>T	p.Lys222Asn	missense_variant	2/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;T;T;.
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.9	L;L;.;L
MutationTaster	Benign	0.048	P;P;P;P;P
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;.;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.031	D;.;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.97	D;D;.;D
Vest4		0.16
MutPred		0.45		Gain of catalytic residue at L223 (P = 0.0056);Gain of catalytic residue at L223 (P = 0.0056);Gain of catalytic residue at L223 (P = 0.0056);Gain of catalytic residue at L223 (P = 0.0056);
MVP		0.88
MPC		0.34
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.58
gMVP		0.53

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: chr14-75515693;