Submissions for variant NM_000535.7(PMS2):c.230A>C (p.Glu77Ala)

gnomAD frequency: 0.00007  dbSNP: rs777095030

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477451	SCV000552072	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000481770	SCV000566627	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in pediatric cancer patients (Chan 2018); This variant is associated with the following publications: (PMID: 30455982, 12606120)
Color Diagnostics, LLC DBA Color Health	RCV000776176	SCV000911288	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 77 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast cancer (PMID: 33471991, 36200007), and in an individual affected with an unspecified childhood tumor (PMID: 30455982). This variant has been identified in 17/250862 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.
Ambry Genetics	RCV000776176	SCV001175963	likely benign	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Sema4, Sema4	RCV000776176	SCV002530286	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268089	SCV002550758	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000481770	SCV004042289	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	PMS2: BP1, BP4
All of Us Research Program, National Institutes of Health	RCV004001885	SCV004842143	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 77 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 17/250862 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481770	SCV001551242	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Glu77Ala variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs777095030) as with uncertain significance allele, and in the ClinVar database as uncertain significance by Invitae and GeneDx. The variant was identified in control databases in 17 of 245846 chromosomes (1 homozygous) at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). It was observed in the South Asian population in 17 of 30782 chromosomes (freq: 0.0006); but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Glu77 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.