14-75046760-A-G

Position:

chr14-75046760-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040108.2(MLH3):c.2896T>C(p.Ser966Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,142 control chromosomes in the GnomAD database, including 341 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 31 hom., cov: 32)

Exomes 𝑓: 0.017 ( 310 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.373

Variant links:

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]

MLH3 links:

MLH3 (HGNC:):

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019047856).

BP6

Variant 14-75046760-A-G is Benign according to our data. Variant chr14-75046760-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 220963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75046760-A-G is described in Lovd as [Benign]. Variant chr14-75046760-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0115 (1751/152338) while in subpopulation SAS AF= 0.0352 (170/4828). AF 95% confidence interval is 0.0309. There are 31 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1751 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.2896T>C	p.Ser966Pro	missense_variant	2/13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.2896T>C	p.Ser966Pro	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020.2		Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1754

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00241

Gnomad AMI

AF:

0.175

Gnomad AMR

AF:

0.00995

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.00415

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0149

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.0156

AC:

3912

AN:

251224

Hom.:

AF XY:

0.0178

AC XY:

2419

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00677

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0415

Gnomad FIN exome

AF:

0.00522

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0167

AC:

24355

AN:

1461804

Hom.:

310

Cov.:

AF XY:

0.0178

AC XY:

12916

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00176

Gnomad4 AMR exome

AF:

0.00776

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0420

Gnomad4 FIN exome

AF:

0.00556

Gnomad4 NFE exome

AF:

0.0164

Gnomad4 OTH exome

AF:

0.0169

GnomAD4 genome

AF:

0.0115

AC:

1751

AN:

152338

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

851

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00241

Gnomad4 AMR

AF:

0.00993

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0352

Gnomad4 FIN

AF:

0.00415

Gnomad4 NFE

AF:

0.0149

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.0159

AC:

1927

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0185

EpiControl

AF:

0.0201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
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. -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MLH3 p.Ser966Pro variant was identified in the literature, however the frequency of this variant in an affected population was not provided. In a study by Talseth-Palmer et al., targeted NGS showed variant c.2896T>C to be a benign variation (Talseth-Palmer_2016_PMID: 26811195). The variant was identified in dbSNP (ID: rs17782839) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹. In ClinVar, there were two submissions: benign by Invitae and likely benign by Illumina Clinical Services Laboratory with the associated conditions of Lynch syndrome and MLH3-Related Lynch Syndrome. The variant was also found in Clinvitae and LOVD 3.0 databases. The variant was not identified in Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 4160 of 282636 chromosomes (59 homozygous) at a frequency of 0.014719 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1271 of 30610 chromosomes (freq: 0.04152), Ashkenazi Jewish in 238 of 10366 chromosomes (freq: 2296), European (non-Finnish) in 2128 of 128974 chromosomes (freq: 0.0165), Other in 110 of 7218 chromosomes (freq: 0.01524), Latino in 241 of 35430 chromosomes (freq: 0.006802), European (Finnish) in 126 of 25122 chromosomes (freq: 0.005016), African in 43 of 24962 chromosomes (freq: 0.001723), and East Asian in 3 of 19954 chromosomes (freq: 0.00015). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Ser966Pro residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.53

DANN

Benign

0.74

DEOGEN2

Benign

0.078

T;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.37

T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;N;.;N

PrimateAI

Benign

0.26

PROVEAN

Benign

1.6

N;.;N;N

REVEL

Benign

0.13

Sift

Benign

0.97

T;.;T;T

Sift4G

Benign

0.38

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.028

MPC

0.13

ClinPred

0.00068

GERP RS

1.3

Varity_R

0.039

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over