rs28756981

chr14-75048965-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040108.2(MLH3):c.691A>C(p.Lys231Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,400 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. K231E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 33)
  • Exomes 𝑓: 0.017 (271 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.16

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=0.0039312243).
• BP6: Variant 14-75048965-T-G is Benign according to our data. Variant chr14-75048965-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 220781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75048965-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0129 (1960/152328) while in subpopulation NFE AF= 0.0193 (1310/68026). AF 95% confidence interval is 0.0184. There are 18 homozygotes in gnomad4. There are 970 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1960 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.691A>C	p.Lys231Gln	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.691A>C	p.Lys231Gln	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.691A>C	p.Lys231Gln	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.691A>C	p.Lys231Gln	missense_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152210 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0193

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.0121 AC: 3016 AN: 249362 Hom.: 35 AF XY: 0.0122 AC XY: 1647 AN XY: 135102

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00938

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000394

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0186

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0172 AC: 25160 AN: 1461072 Hom.: 271 Cov.: 35 AF XY: 0.0168 AC XY: 12199 AN XY: 726786

Gnomad4 AFR exome AF: 0.00234

Gnomad4 AMR exome AF: 0.00563

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000709

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0129 AC: 1960 AN: 152328 Hom.: 18 Cov.: 33 AF XY: 0.0130 AC XY: 970 AN XY: 74480

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.0100

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0193

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0173 Hom.: 49

Bravo AF: 0.0120

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0192 AC: 165

ExAC AF: 0.0123 AC: 1488

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.77	T;T;T;.
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L;L;.;L
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.20
Sift	Benign	0.26	T;.;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.53	P;B;.;P
Vest4		0.10
MPC		0.14
ClinPred		0.015	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.45

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: rs28756981; hg19: chr14-75515668; COSMIC: COSV104587310; COSMIC: COSV104587310;