rs761913816

chr7-5989955-T-C

Variant summary

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

The NM_000535.7(PMS2):c.989A>G(p.Glu330Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000224 in 1,430,096 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E330Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense, splice_region
• Scores: Splicing: ADA: 0.00008512
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 4.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.989A>G	p.Glu330Gly	missense_variant, splice_region_variant	10/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.989A>G	p.Glu330Gly	missense_variant, splice_region_variant	10/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 247842 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 133998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000224 AC: 32 AN: 1430096 Hom.: 0 Cov.: 26 AF XY: 0.0000169 AC XY: 12 AN XY: 712098

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000285

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with MSI-H colorectal cancer whose tumor demonstrated loss of MLH1 and PMS2 on immunohistochemistry (Wang et al., 2020); This variant is associated with the following publications: (PMID: 11574484, 31992580) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2023	In the published literature, this variant has been reported in an individual with colorectal cancer, whose tumor exhibited microsatellite instability, and loss of MLH1 and PMS2 staining (PMID: 31615547 (2020)). The frequency of this variant in the general population, 0.000027 (3/112460 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 05, 2023	This missense variant replaces glutamic acid with glycine at codon 330 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset colorectal cancer, whose tumor displayed high microsatellite instability and loss of MLH1 and PMS2 protein via immunohistochemistry analysis (PMID: 31992580). MLH1 methylation status was not available for this tumor. This variant has been identified in 4/247842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 20, 2022	The p.E330G variant (also known as c.989A>G) is located in coding exon 10 of the PMS2 gene. The glutamic acid at codon 330 is replaced by glycine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 10. This variant was identified in a proband diagnosed with MSI-H colorectal cancer at the age of 45 that showed loss of MLH1 and PMS2 staining on immunohistochemistry, but MLH1 promoter hypermethylation status was not available (Wang Q et al. J Med Genet, 2020 07;57:487-499). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 23, 2023

This missense variant replaces glutamic acid with glycine at codon 330 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset colorectal cancer, whose tumor displayed high microsatellite instability and loss of MLH1 and PMS2 protein via immunohistochemistry analysis (PMID: 31992580). MLH1 methylation status was not available for this tumor. This variant has been identified in 4/247842 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 330 of the PMS2 protein (p.Glu330Gly). This variant is present in population databases (rs761913816, gnomAD 0.003%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 31992580). ClinVar contains an entry for this variant (Variation ID: 567236). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Lynch syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;.;T;.
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.4	D;D;.;.;.
REVEL	Uncertain	0.58
Sift	Benign	0.22	T;D;.;.;.
Sift4G	Benign	0.25	T;T;.;.;.
Polyphen		0.12	B;B;.;.;B
Vest4		0.31
MutPred		0.53		Loss of stability (P = 0.0232);.;.;.;.;
MVP		0.88
MPC		0.069
ClinPred		0.44	T
GERP RS		3.2
Varity_R		0.47
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000085
dbscSNV1_RF	Benign	0.0060
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: rs761913816; hg19: chr7-6029586;