14-75047180-T-C

Position:

• chr14-75047180-T-C

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.2476A>G​(p.Asn826Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,180 control chromosomes in the GnomAD database, including 803,856 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74524 hom., cov: 32)
  • Exomes 𝑓: 1.0 (729332 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.319

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=1.6601552E-6).
• BP6: Variant 14-75047180-T-C is Benign according to our data. Variant chr14-75047180-T-C is described in ClinVar as [Benign]. Clinvar id is 257251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75047180-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2476A>G	p.Asn826Asp	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.2476A>G	p.Asn826Asp	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020	P1
MLH3	ENST00000380968.6	c.2476A>G	p.Asn826Asp	missense_variant	2/12	1		ENSP00000370355
MLH3	ENST00000556257.5	c.2476A>G	p.Asn826Asp	missense_variant	2/7	5		ENSP00000451540
MLH3	ENST00000555671.1	n.22A>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150566 AN: 152240 Hom.: 74466 Cov.: 32

Gnomad AFR AF: 0.962

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.997 AC: 250717 AN: 251402 Hom.: 125027 AF XY: 0.998 AC XY: 135612 AN XY: 135882

Gnomad AFR exome AF: 0.963

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.999 AC: 1460221 AN: 1461822 Hom.: 729332 Cov.: 51 AF XY: 0.999 AC XY: 726535 AN XY: 727214

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.989 AC: 150683 AN: 152358 Hom.: 74524 Cov.: 32 AF XY: 0.989 AC XY: 73704 AN XY: 74506

Gnomad4 AFR AF: 0.962

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.990

Alfa AF: 0.997 Hom.: 107439

Bravo AF: 0.987

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.967 AC: 4260

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 0.997 AC: 121019

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	-	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

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 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.40
DANN	Benign	0.69
DEOGEN2	Benign	0.089	T;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.034	T;T;T;.
MetaRNN	Benign	0.0000017	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.26	N;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.85	T;.;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.017
MPC		0.11
ClinPred		0.00016	T
GERP RS		1.3
Varity_R		0.041
gMVP		0.094

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: rs175081; hg19: chr14-75513883;