rs17782839

Variant names:

• chr14-75046760-A-G
• rs17782839
• NM_001040108.2:c.2896T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-75046760-A-G
• chr14-75046760-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S966T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.017 (310 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.373
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• colorectal cancer, hereditary nonpolyposis, type 7

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 220963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2896T>C	p.Ser966Pro	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.2896T>C	p.Ser966Pro	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1754 AN: 152220 Hom.: 31 Cov.: 32

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

GnomAD2 exomes AF: 0.0156 AC: 3912 AN: 251224 AF XY: 0.0178

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 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.: 34 AF XY: 0.0178 AC XY: 12916 AN XY: 727206

African (AFR) AF: 0.00176 AC: 59 AN: 33480

American (AMR) AF: 0.00776 AC: 347 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 563 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.0420 AC: 3625 AN: 86252

European-Finnish (FIN) AF: 0.00556 AC: 297 AN: 53414

Middle Eastern (MID) AF: 0.0369 AC: 213 AN: 5766

European-Non Finnish (NFE) AF: 0.0164 AC: 18227 AN: 1111944

Other (OTH) AF: 0.0169 AC: 1018 AN: 60396

GnomAD4 genome AF: 0.0115 AC: 1751 AN: 152338 Hom.: 31 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74490

African (AFR) AF: 0.00241 AC: 100 AN: 41568

American (AMR) AF: 0.00993 AC: 152 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0352 AC: 170 AN: 4828

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1017 AN: 68046

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0145 Hom.: 83

Bravo AF: 0.0113

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0159 AC: 1927

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 “With Likely benign allele”. 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. -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Endometrial carcinoma Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.49	T
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	N
LIST_S2	Benign	0.37	T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;.;N
PhyloP100		-0.37
PrimateAI	Benign	0.26	T
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	T
GERP RS		1.3
PromoterAI		0.0048	Neutral
Varity_R		0.039
gMVP		0.16
Mutation Taster		=299/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17782839; hg19: chr14-75513463; COSMIC: COSV104587495;