chr14-75047125-G-A

Position:

• chr14-75047125-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.2531C>T​(p.Pro844Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 1,613,336 control chromosomes in the GnomAD database, including 164,611 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13962 hom., cov: 33)
  • Exomes 𝑓: 0.45 (150649 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.89

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=4.402101E-4).
• BP6: Variant 14-75047125-G-A is Benign according to our data. Variant chr14-75047125-G-A is described in ClinVar as [Benign]. Clinvar id is 257252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047125-G-A is described in Lovd as [Benign]. Variant chr14-75047125-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2531C>T	p.Pro844Leu	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2531C>T	p.Pro844Leu	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.2531C>T	p.Pro844Leu	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.2531C>T	p.Pro844Leu	missense_variant	2/7	5
MLH3	ENST00000555671.1	n.77C>T		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64203 AN: 151946 Hom.: 13947 Cov.: 33

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.484

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.434

GnomAD3 exomes AF: 0.404 AC: 101408 AN: 251230 Hom.: 22003 AF XY: 0.416 AC XY: 56468 AN XY: 135818

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.464

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.449 AC: 655716 AN: 1461272 Hom.: 150649 Cov.: 48 AF XY: 0.450 AC XY: 327339 AN XY: 726962

Gnomad4 AFR exome AF: 0.401

Gnomad4 AMR exome AF: 0.253

Gnomad4 ASJ exome AF: 0.485

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.465

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.466

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.423 AC: 64254 AN: 152064 Hom.: 13962 Cov.: 33 AF XY: 0.421 AC XY: 31281 AN XY: 74354

Gnomad4 AFR AF: 0.400

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.152

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.441

Alfa AF: 0.448 Hom.: 24726

Bravo AF: 0.411

TwinsUK AF: 0.473 AC: 1755

ALSPAC AF: 0.455 AC: 1754

ESP6500AA AF: 0.403 AC: 1776

ESP6500EA AF: 0.463 AC: 3981

ExAC AF: 0.412 AC: 50076

Asia WGS AF: 0.364 AC: 1265 AN: 3478

EpiCase AF: 0.459

EpiControl AF: 0.457

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 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, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 19808033) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.65	T;T;T;.
MetaRNN	Benign	0.00044	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L;L;.;L
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.0	D;.;D;D
REVEL	Benign	0.11
Sift	Benign	0.29	T;.;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.076
MPC		0.10
ClinPred		0.0085	T
GERP RS		4.1
Varity_R		0.080
gMVP		0.22

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: rs175080; hg19: chr14-75513828; COSMIC: COSV53153237; COSMIC: COSV53153237;