Submissions for variant NM_000535.7(PMS2):c.944G>A (p.Arg315Gln)

gnomAD frequency: 0.00006  dbSNP: rs116314131

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163216	SCV000213739	likely benign	Hereditary cancer-predisposing syndrome	2023-01-25	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.
Invitae	RCV000524485	SCV000254621	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 315 of the PMS2 protein (p.Arg315Gln). This variant is present in population databases (rs116314131, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer, sarcoma, and/or biliary tract cancer (PMID: 25503501, 27498913, 36243179). ClinVar contains an entry for this variant (Variation ID: 184092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000197131	SCV000266222	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000679365	SCV000279135	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast cancer, sarcoma, or a family history of ovarian cancer, but also observed in unaffected controls (Maxwell 2015, Shirts 2016, Ballinger 2016, Nikitin 2020, Mizukami 2020); This variant is associated with the following publications: (PMID: 25503501, 26845104, 27498913, 32547938, 32980694, 11574484)
Counsyl	RCV000412322	SCV000487977	uncertain significance	Lynch syndrome 4	2015-12-07	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000197131	SCV000700120	uncertain significance	Lynch syndrome	2016-10-01	criteria provided, single submitter	research	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 66 year old female with uterine cancer diagnosed at age 56 and a family history of colon cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
PreventionGenetics, part of Exact Sciences	RCV003389705	SCV000806228	uncertain significance	PMS2-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	The PMS2 c.944G>A variant is predicted to result in the amino acid substitution p.Arg315Gln. This variant has been reported in an individual with early-onset breast cancer who also had a deleterious variant in CHEK2 (Table 2, Maxwell et al., 2015. PubMed ID: 25503501), an individual with a history of ovarian cancer (Table S1, Shirts et al., 2016. PubMed ID: 26845104), and an individual with breast cancer (Table S2, Nikitin et al. 2020. PubMed ID: 32547938). It has also been reported in a control from a pancreatic cancer cohort study (Table S6, Mizukami et al. 2020. PubMed ID: 32980694). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6031648-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184092/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Color Diagnostics, LLC DBA Color Health	RCV000163216	SCV000909664	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 315 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 sarcoma (PMID: 27498913), an individual affected with uterine cancer with a family history of ovarian cancer (ClinVar RCV000197131.6), and a third individual affected with early-onset breast cancer who also has a pathogenic CHEK2 mutation (PMID: 25503501). This variant also has been reported in an unaffected individual with a family history of ovarian cancer (PMID: 26845104) and in a pancreatic case-control study where it was detected in several unaffected individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 5/251260 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780629	SCV000918059	uncertain significance	not specified	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.944G>A (p.Arg315Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251260 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.944G>A has been reported in the literature in an individual with breast cancer who also carried a pathogenic (CHEK2 c.1283C>T, p.Ser428Phe) variant (Maxwell_2014), as well as in a patient with ovarian cancer (Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV000412322	SCV001326416	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780629	SCV002760378	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002492646	SCV002778550	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-04-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412322	SCV004019794	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000412322	SCV004205379	uncertain significance	Lynch syndrome 4	2024-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679365	SCV004219037	uncertain significance	not provided	2023-08-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 32547938 (2020), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PMS2)), including one affected individual who co-carried a pathogenic CHEK2 variant (PMID: 25503501 (2015)). This variant has also been observed in an individual with a family history of ovarian cancer (PMID: 26845104 (2016)), and in several unaffected control individuals (PMIDs: 36243179 (2022), 33471991 (2021), 32980694 (2020)). The frequency of this variant in the general population, 0.000035 (4/113696 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 benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492673	SCV004239607	uncertain significance	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000197131	SCV004839875	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 315 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 sarcoma (PMID: 27498913), an individual affected with uterine cancer with a family history of ovarian cancer (ClinVar RCV000197131.6), and a third individual affected with early-onset breast cancer who also has a pathogenic CHEK2 mutation (PMID: 25503501). This variant also has been reported in an unaffected individual with a family history of ovarian cancer (PMID: 26845104) and in a pancreatic case-control study where it was detected in several unaffected individuals and absent in cancer cases (PMID: 32980694). This variant has been identified in 5/251260 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	RCV000679365	SCV001551954	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Arg315Gln variant was identified in 2 of 3480 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Maxwell 2014, Shirts 2016). The variant was also identified in dbSNP (ID: rs116314131) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx, Coulsyl and two clinical laboratories). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 6 of 277006 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24006 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), and European in 4 of 126670 chromosomes (freq: 0.00003); it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg315 residue is 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.