rs766847331

Variant names:

• chr14-75046936-T-A
• rs766847331
• NM_001040108.2:c.2720A>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001040108.2(MLH3):​c.2720A>T​(p.Lys907Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.39

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26661274).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2720A>T	p.Lys907Ile	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.2720A>T	p.Lys907Ile	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251306 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461820 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K907I variant (also known as c.2720A>T), located in coding exon 1 of the MLH3 gene, results from an A to T substitution at nucleotide position 2720. The lysine at codon 907 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 907 of the MLH3 protein (p.Lys907Ile). This variant is present in population databases (rs766847331, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 410890). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.81	T;T;T;.
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L;L;.;L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.7	D;.;N;D
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;.;D;D
Sift4G	Uncertain	0.015	D;D;T;D
Polyphen		0.78	P;P;.;P
Vest4		0.26
MutPred		0.34		Loss of ubiquitination at K907 (P = 0.0019);Loss of ubiquitination at K907 (P = 0.0019);Loss of ubiquitination at K907 (P = 0.0019);Loss of ubiquitination at K907 (P = 0.0019);
MVP		0.89
MPC		0.38
ClinPred		0.75	D
GERP RS		3.5
Varity_R		0.13
gMVP		0.34

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: rs766847331; hg19: chr14-75513639;