rs17102999

chr14-75046831-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040108.2(MLH3):c.2825C>T(p.Thr942Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00475 in 1,614,108 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T942T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (154 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.879

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017848909).
• BP6: Variant 14-75046831-G-A is Benign according to our data. Variant chr14-75046831-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75046831-G-A is described in Lovd as [Likely_pathogenic].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.062 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2825C>T	p.Thr942Ile	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2825C>T	p.Thr942Ile	missense_variant	2/13	5	NM_001040108.2	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1584 AN: 152218 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0128 AC: 3226 AN: 251340 Hom.: 90 AF XY: 0.0109 AC XY: 1484 AN XY: 135848

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.0474

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.0534

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.00416 AC: 6082 AN: 1461772 Hom.: 154 Cov.: 34 AF XY: 0.00390 AC XY: 2837 AN XY: 727190

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0550

Gnomad4 SAS exome AF: 0.00272

Gnomad4 FIN exome AF: 0.0134

Gnomad4 NFE exome AF: 0.000326

Gnomad4 OTH exome AF: 0.00583

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152336 Hom.: 54 Cov.: 32 AF XY: 0.0130 AC XY: 965 AN XY: 74500

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.0654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00332 Hom.: 32

Bravo AF: 0.0118

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00993 AC: 1206

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2018

This variant is associated with the following publications: (PMID: 16885347, 24759751, 20981092) -

MLH3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.86
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.78	T;T;T;.
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.19
Sift	Benign	0.24	T;.;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.085	B;P;.;B
Vest4		0.049
MPC		0.11
ClinPred		0.0067	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.27

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: rs17102999; hg19: chr14-75513534; COSMIC: COSV104587494; COSMIC: COSV104587494;