rs778414174

Variant names:

• chr14-75046589-T-C
• rs778414174
• NM_001040108.2:c.3067A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040108.2(MLH3):​c.3067A>G​(p.Ser1023Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.214

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06018275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.3067A>G	p.Ser1023Gly	missense_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.3067A>G	p.Ser1023Gly	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1023G variant (also known as c.3067A>G), located in coding exon 1 of the MLH3 gene, results from an A to G substitution at nucleotide position 3067. The serine at codon 1023 is replaced by glycine, 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

Apr 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 544277). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. This variant is present in population databases (rs778414174, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1023 of the MLH3 protein (p.Ser1023Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.091	T;.;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T;T;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.060	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M;M;.;M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N;.;N;N
REVEL	Benign	0.079
Sift	Benign	0.16	T;.;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.057
MutPred		0.25		Gain of catalytic residue at F1021 (P = 2e-04);Gain of catalytic residue at F1021 (P = 2e-04);Gain of catalytic residue at F1021 (P = 2e-04);Gain of catalytic residue at F1021 (P = 2e-04);
MVP		0.70
MPC		0.092
ClinPred		0.042	T
GERP RS		1.3
Varity_R		0.031
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs778414174; hg19: chr14-75513292;