NM_001040108.2:c.2533A>G

Variant names:

• chr14-75047123-T-C
• rs28756992
• NM_001040108.2:c.2533A>G

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.2533A>G​(p.Ser845Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,614,184 control chromosomes in the GnomAD database, including 146 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. S845N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (114 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.182
• Publications: 18 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=0.0028146803).
• BP6: Variant 14-75047123-T-C is Benign according to our data. Variant chr14-75047123-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 220674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2259/152354) while in subpopulation AFR AF = 0.0316 (1315/41584). AF 95% confidence interval is 0.0302. There are 32 homozygotes in GnomAd4. There are 1084 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2533A>G	p.Ser845Gly	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.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 12	1		ENSP00000370355.3
MLH3	ENST00000556257.5	c.2533A>G	p.Ser845Gly	missense_variant	Exon 2 of 7	5		ENSP00000451540.1
MLH3	ENST00000555671.1	n.79A>G		non_coding_transcript_exon_variant	Exon 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2258 AN: 152236 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0109 AC: 2746 AN: 251264 AF XY: 0.0116

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00735

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00982 AC: 14362 AN: 1461830 Hom.: 114 Cov.: 34 AF XY: 0.0102 AC XY: 7442 AN XY: 727210

African (AFR) AF: 0.0349 AC: 1170 AN: 33478

American (AMR) AF: 0.00639 AC: 286 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 77 AN: 26132

East Asian (EAS) AF: 0.0101 AC: 401 AN: 39684

South Asian (SAS) AF: 0.0267 AC: 2303 AN: 86256

European-Finnish (FIN) AF: 0.00155 AC: 83 AN: 53412

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5768

European-Non Finnish (NFE) AF: 0.00833 AC: 9264 AN: 1111982

Other (OTH) AF: 0.0111 AC: 669 AN: 60394

GnomAD4 genome AF: 0.0148 AC: 2259 AN: 152354 Hom.: 32 Cov.: 32 AF XY: 0.0145 AC XY: 1084 AN XY: 74516

African (AFR) AF: 0.0316 AC: 1315 AN: 41584

American (AMR) AF: 0.00948 AC: 145 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0102 AC: 53 AN: 5190

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00788 AC: 536 AN: 68030

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.0106 Hom.: 89

Bravo AF: 0.0158

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.0116 AC: 1410

Asia WGS AF: 0.0190 AC: 66 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MLH3 p.Ser845Gly variant was identified in 5 of 934 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer and was also present in 8 of 994 control chromosomes (frequency: 0.008) from healthy individuals (de Jong_2004_PMID:15193445). The variant was identified in dbSNP (ID: rs28756992), ClinVar (classified as likely benign by Illumina and as benign by Invitae for Lynch syndrome) and LOVD 3.0 (classified as a VUS) but was not identified in Cosmic. The variant was identified in control databases in 3189 of 282666 chromosomes (38 homozygous) at a frequency of 0.011282 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: African in 791 of 24898 chromosomes (freq: 0.03177), South Asian in 856 of 30612 chromosomes (freq: 0.02796), East Asian in 240 of 19952 chromosomes (freq: 0.01203), Other in 76 of 7214 chromosomes (freq: 0.01054), European (non-Finnish) in 950 of 129064 chromosomes (freq: 0.007361), Latino in 217 of 35438 chromosomes (freq: 0.006123), Ashkenazi Jewish in 22 of 10368 chromosomes (freq: 0.002122), and European (Finnish) in 37 of 25120 chromosomes (freq: 0.001473). The p.Ser845 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 22, 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	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.29
DANN	Benign	0.61
DEOGEN2	Benign	0.092	T;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.52	T;T;T;.
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N;N;.;N
PhyloP100		-0.18
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.57	T;.;T;T
Sift4G	Benign	0.95	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.047
MPC		0.091
ClinPred		0.0026	T
GERP RS		-7.2
PromoterAI		0.018	Neutral
Varity_R		0.034
gMVP		0.18
Mutation Taster		=99/1	polymorphism

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: rs28756992; hg19: chr14-75513826; COSMIC: COSV104587544;