14-75047018-G-C

Position:

• chr14-75047018-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001040108.2(MLH3):​c.2638C>G​(p.Leu880Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L880L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.721

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05520761).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000188 (275/1461840) while in subpopulation SAS AF= 0.00102 (88/86256). AF 95% confidence interval is 0.000847. There are 2 homozygotes in gnomad4_exome. There are 164 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2638C>G	p.Leu880Val	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2638C>G	p.Leu880Val	missense_variant	2/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.2638C>G	p.Leu880Val	missense_variant	2/12	1
MLH3	ENST00000556257.5	c.2638C>G	p.Leu880Val	missense_variant	2/7	5
MLH3	ENST00000555671.1	n.184C>G		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000243 AC: 61 AN: 251170 Hom.: 1 AF XY: 0.000332 AC XY: 45 AN XY: 135738

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1461840 Hom.: 2 Cov.: 34 AF XY: 0.000226 AC XY: 164 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000147

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	This sequence change replaces leucine with valine at codon 880 of the MLH3 protein (p.Leu880Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs201453923, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 09, 2023	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 880 of the MLH3 protein (p.Leu880Val). This variant is present in population databases (rs201453923, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense variant c.2638C>G (p.Leu880Val) in MLH3 gene has been reported previously in individual(s) affected with MLH3-associated cancer (Raskin et al. 2017). This variant is present with an allele frequency of 0.02% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Leu880Val in MLH3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 880 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2022	The p.L880V variant (also known as c.2638C>G), located in coding exon 1 of the MLH3 gene, results from a C to G substitution at nucleotide position 2638. The leucine at codon 880 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in an individual whose colon tumor was microsatellite stable and demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

Endometrial carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 05, 2023

This sequence change replaces leucine with valine at codon 880 of the MLH3 protein (p.Leu880Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs201453923, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.093	T;.;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.86	D;T;D;.
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.3	L;L;.;L
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.020	D;.;D;D
Sift4G	Uncertain	0.024	D;D;T;D
Polyphen		0.012	B;P;.;B
Vest4		0.085
MVP		0.83
MPC		0.12
ClinPred		0.046	T
GERP RS		3.8
Varity_R		0.079
gMVP		0.37

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: rs201453923; hg19: chr14-75513721; COSMIC: COSV99470139; COSMIC: COSV99470139;