14-75048990-C-T

Variant names:

• chr14-75048990-C-T
• rs28756980
• NM_001040108.2:c.666G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001040108.2(MLH3):​c.666G>A​(p.Lys222Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,986 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (68 hom., cov: 33)
  • Exomes 𝑓: 0.011 (166 hom.)
• Consequence: MLH3 NM_001040108.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.967

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-75048990-C-T is Benign according to our data. Variant chr14-75048990-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 314391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.967 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.666G>A	p.Lys222Lys	synonymous_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.666G>A	p.Lys222Lys	synonymous_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.666G>A	p.Lys222Lys	synonymous_variant	Exon 2 of 12	1		ENSP00000370355.3
MLH3	ENST00000556257.5	c.666G>A	p.Lys222Lys	synonymous_variant	Exon 2 of 7	5		ENSP00000451540.1
MLH3	ENST00000553263.1	c.*179G>A		downstream_gene_variant		2		ENSP00000451192.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3128 AN: 152168 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00795

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0133 AC: 3319 AN: 250200 Hom.: 49 AF XY: 0.0141 AC XY: 1909 AN XY: 135528

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00727

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0123

Gnomad SAS exome AF: 0.0369

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00736

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.0109 AC: 15905 AN: 1461700 Hom.: 166 Cov.: 35 AF XY: 0.0115 AC XY: 8356 AN XY: 727122

Gnomad4 AFR exome AF: 0.0522

Gnomad4 AMR exome AF: 0.00763

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.0357

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00835

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0206 AC: 3132 AN: 152286 Hom.: 68 Cov.: 33 AF XY: 0.0203 AC XY: 1508 AN XY: 74458

Gnomad4 AFR AF: 0.0503

Gnomad4 AMR AF: 0.0111

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0413

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00795

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00994 Hom.: 16

Bravo AF: 0.0215

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely 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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Jun 02, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.4
DANN	Benign	0.78

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: rs28756980; hg19: chr14-75515693; COSMIC: COSV104587316; COSMIC: COSV104587316;