rs878854162

Positions:

• chr14-75047798-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040108.2(MLH3):​c.1858T>G​(p.Ser620Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.820

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10921869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.1858T>G	p.Ser620Ala	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.1858T>G	p.Ser620Ala	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.1858T>G	p.Ser620Ala	missense_variant	2/12	1		ENSP00000370355.3
MLH3	ENST00000556257.5	c.1858T>G	p.Ser620Ala	missense_variant	2/7	5		ENSP00000451540.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2024

The p.S620A variant (also known as c.1858T>G), located in coding exon 1 of the MLH3 gene, results from a T to G substitution at nucleotide position 1858. The serine at codon 620 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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. -

Colorectal cancer, hereditary nonpolyposis, type 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 18, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 238245). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 620 of the MLH3 protein (p.Ser620Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.68	T;T;T;.
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.;M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.041
Sift	Benign	0.13	T;.;T;T
Sift4G	Uncertain	0.039	D;D;D;D
Polyphen		0.35	B;P;.;B
Vest4		0.082
MutPred		0.23		Gain of catalytic residue at E616 (P = 0.0044);Gain of catalytic residue at E616 (P = 0.0044);Gain of catalytic residue at E616 (P = 0.0044);Gain of catalytic residue at E616 (P = 0.0044);
MVP		0.57
MPC		0.12
ClinPred		0.27	T
GERP RS		1.8
Varity_R		0.094
gMVP		0.18

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: rs878854162; hg19: chr14-75514501;