rs17782839

Positions:

• chr14-75046760-A-G
• chr14-75046760-A-T

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.2896T>C​(p.Ser966Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,614,142 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. S966L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.017 (310 hom.)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.373

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=0.0019047856).
• BP6: Variant 14-75046760-A-G is Benign according to our data. Variant chr14-75046760-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 220963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75046760-A-G is described in Lovd as [Benign]. Variant chr14-75046760-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0115 (1751/152338) while in subpopulation SAS AF= 0.0352 (170/4828). AF 95% confidence interval is 0.0309. There are 31 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1751 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.2896T>C	p.Ser966Pro	missense_variant	2/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.2896T>C	p.Ser966Pro	missense_variant	2/13	5	NM_001040108.2	P1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1754 AN: 152220 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0156 AC: 3912 AN: 251224 Hom.: 55 AF XY: 0.0178 AC XY: 2419 AN XY: 135778

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0415

Gnomad FIN exome AF: 0.00522

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0167 AC: 24355 AN: 1461804 Hom.: 310 Cov.: 34 AF XY: 0.0178 AC XY: 12916 AN XY: 727206

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00776

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0420

Gnomad4 FIN exome AF: 0.00556

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0115 AC: 1751 AN: 152338 Hom.: 31 Cov.: 32 AF XY: 0.0114 AC XY: 851 AN XY: 74490

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0352

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0155 Hom.: 48

Bravo AF: 0.0113

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0159 AC: 1927

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0201

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, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MLH3 p.Ser966Pro variant was identified in the literature, however the frequency of this variant in an affected population was not provided. In a study by Talseth-Palmer et al., targeted NGS showed variant c.2896T>C to be a benign variation (Talseth-Palmer_2016_PMID: 26811195). The variant was identified in dbSNP (ID: rs17782839) as “With Likely benign allele”. In ClinVar, there were two submissions: benign by Invitae and likely benign by Illumina Clinical Services Laboratory with the associated conditions of Lynch syndrome and MLH3-Related Lynch Syndrome. The variant was also found in Clinvitae and LOVD 3.0 databases. The variant was not identified in Cosmic, MutDB, and UMD-LSDB databases. The variant was identified in control databases in 4160 of 282636 chromosomes (59 homozygous) at a frequency of 0.014719 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1271 of 30610 chromosomes (freq: 0.04152), Ashkenazi Jewish in 238 of 10366 chromosomes (freq: 2296), European (non-Finnish) in 2128 of 128974 chromosomes (freq: 0.0165), Other in 110 of 7218 chromosomes (freq: 0.01524), Latino in 241 of 35430 chromosomes (freq: 0.006802), European (Finnish) in 126 of 25122 chromosomes (freq: 0.005016), African in 43 of 24962 chromosomes (freq: 0.001723), and East Asian in 3 of 19954 chromosomes (freq: 0.00015). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Ser966Pro residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.53
DANN	Benign	0.74
DEOGEN2	Benign	0.078	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.37	T;T;T;.
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.97	T;.;T;T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;B;.;B
Vest4		0.028
MPC		0.13
ClinPred		0.00068	T
GERP RS		1.3
Varity_R		0.039
gMVP		0.16

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: rs17782839; hg19: chr14-75513463; COSMIC: COSV104587495; COSMIC: COSV104587495;