rs121908439

chr14-75032069-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001040108.2(MLH3):c.3826T>C(p.Trp1276Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000102 in 1,571,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: MLH3 NM_001040108.2 missense, splice_region
• Scores: Splicing: ADA: 0.00002373
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: -3.48

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038110465).
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.3826T>C	p.Trp1276Arg	missense_variant, splice_region_variant	8/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.3826T>C	p.Trp1276Arg	missense_variant, splice_region_variant	8/13	5	NM_001040108.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251418 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000986 AC: 14 AN: 1419220 Hom.: 0 Cov.: 26 AF XY: 0.0000127 AC XY: 9 AN XY: 708796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000932

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000832 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 07, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2018	This sequence change replaces tryptophan with arginine at codon 1276 of the MLH3 protein (p.Trp1276Arg). The tryptophan residue is weakly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs121908439, ExAC 0.03%). 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. This variant has been reported not to substantially affect MLH3 protein function (PMID: 18521850). This variant has been observed in individuals affected with colorectal cancers (PMID: 12702580, 16981255). ClinVar contains an entry for this variant (Variation ID: 5564). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The p.W1276R variant (also known as c.3826T>C), located in coding exon 7 of the MLH3 gene, results from a T to C substitution at nucleotide position 3826. The tryptophan at codon 1276 is replaced by arginine, an amino acid with dissimilar properties. This variant segregated with disease in one family with colorectal cancer meeting Amsterdam criteria II; however, it co-occurred with a paternally inherited MSH2 missense variant in all four affected siblings whose tumors were microsatellite stable and demonstrated normal MSH2 protein expression on immunohistochemistry (Liu HX et al. Cancer Res., 2003 Apr;63:1894-9; Lagerstedt Robinson K et al. J. Natl Cancer Inst., 2007 Feb;99:291-9). This alteration did not segregate with disease in one Chinese family with familial esophageal cancer (Liu HX et al. World J. Gastroenterol., 2006 Sep;12:5281-6). In one study, the W1276R variant as part of the MutLγ complex showed normal protein stability and interaction with MLH1 as compared to wild type MLH3; mismatch repair efficiency of the W1276R recombinant protein was also similar to that of wild type MutLγ in vitro (Korhonen MK et al, 2008 Sep;47:803-9). This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	0.0010
Dann	Benign	0.23
DEOGEN2	Benign	0.059	T;.;T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.44	T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-2.5	N;.;N
MutationTaster	Benign	0.0000012	A;A;A;A;A;A
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.5	N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.98	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.033
MutPred		0.67		Gain of catalytic residue at K1280 (P = 0.0101);.;Gain of catalytic residue at K1280 (P = 0.0101);
MVP		0.28
MPC		0.18
ClinPred		0.030	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.016
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: rs121908439; hg19: chr14-75498772;