7-5978689-T-C

Position:

• chr7-5978689-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000535.7(PMS2):​c.2182A>G​(p.Thr728Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. TL728A?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0078 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.57

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010939866).
• BP6: Variant 7-5978689-T-C is Benign according to our data. Variant chr7-5978689-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192223.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=5}. Variant chr7-5978689-T-C is described in Lovd as [Likely_benign]. Variant chr7-5978689-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2182A>G	p.Thr728Ala	missense_variant	13/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2182A>G	p.Thr728Ala	missense_variant	13/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1150 AN: 148006 Hom.: 14 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00344

GnomAD3 exomes AF: 0.00203 AC: 467 AN: 229692 Hom.: 4 AF XY: 0.00152 AC XY: 190 AN XY: 124710

Gnomad AFR exome AF: 0.0286

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.000312

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.00244

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00102 AC: 1460 AN: 1434356 Hom.: 33 Cov.: 30 AF XY: 0.000907 AC XY: 648 AN XY: 714224

Gnomad4 AFR exome AF: 0.0348

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000270

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00781 AC: 1156 AN: 148104 Hom.: 16 Cov.: 32 AF XY: 0.00737 AC XY: 533 AN XY: 72350

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00332

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00341

Alfa AF: 0.00543 Hom.: 1

ExAC AF: 0.00379 AC: 456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2021	Variant summary: PMS2 c.2182A>G (p.Thr728Ala) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 229692 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 408.31 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2182A>G has been reported in the literature in individuals. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 27, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2017	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, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 20, 2024	The p.Thr728Ala variant is not predicted to disrupt the existing acceptor splice site 8bp upstream by any splice site algorithm. The p.Thr728Ala variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Thr728Ala missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The alanine residue at codon 728 of PMS2 is present in Lesser Egyptian jerboa and 2 other mammalian species. The nucleotide c.2182 in PMS2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Benign. -

Lynch syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Pathway Genomics

Oct 30, 2014

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 18, 2020

- -

Lynch syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

May 01, 2018

PMS2 NM_000535.5:c.2182A>G has a 2.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS2 p.Thr728Ala variant was identified in 1 of 192 proband chromosomes (frequency: 0.005) from individuals with pancreatic cancer (Hu 2016). The variant was identified in dbSNP (rs141893001) as “with uncertain significance allele” and ClinVar (classified as benign by Invitae, Ambry Genetics and VU University, likely benign by The Children's Hospital of Philadelphia and the University of Washington and uncertain significance by Integrated Genetics and Pathway Genomics). The variant was identified in control databases in 668 of 260,078 chromosomes (5 homozygous) at a frequency of 0.003 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: African in 582 of 21,634 chromosomes (freq: 0.03), Other in 16 of 6782 chromosomes (freq: 0.002), Latino in 46 of 34,228 chromosomes (freq: 0.001), Ashkenazi Jewish in 3 of 9896 chromosomes (freq: 0.0003), European in 20 of 115,888 chromosomes (freq: 0.0002), South Asian in 1 of 28,826 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian, and Finnish populations. The p.Thr728Ala residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.094	T;.;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T;T;.;T;.;T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N;.;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.51	T;T;.;.;.;T
Sift4G	Benign	0.39	T;T;.;.;.;T
Polyphen		0.0010	B;B;.;.;B;B
Vest4		0.21
MVP		0.79
MPC		1.8
ClinPred		0.0080	T
GERP RS		3.3
Varity_R		0.073
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs141893001; hg19: chr7-6018320; COSMIC: COSV99063705; COSMIC: COSV99063705;