Submissions for variant NM_000535.7(PMS2):c.1004A>G (p.Asn335Ser)

gnomAD frequency: 0.00026  dbSNP: rs200513014

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586586	SCV000149556	likely benign	not provided	2021-06-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28195393, 28135145, 25256751, 24549055, 24728327, 28503720, 27153395, 28596308, 28874130, 28591191, 28873162, 30306255, 27535533, 11574484, 29625052, 31992580)
Invitae	RCV001080700	SCV000166366	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115647	SCV000185908	likely benign	Hereditary cancer-predisposing syndrome	2019-02-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000115647	SCV000537521	likely benign	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586586	SCV000601805	likely benign	not provided	2022-09-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121835	SCV000697275	likely benign	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1004A>G (p.Asn335Ser) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 250652 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-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 Non-Finnish European origin. c.1004A>G has been reported in the literature in individuals affected with different types of cancer including colorectal cancer, breast and/or ovarian cancer, pancreatic cancer, therapy-related myeloid neoplasms, and papillary thyroid cancer (e.g. Harismendy_2013, Castera_2014, Tung_2014, Maxwell_2016, Yurgelun_2017, Rummel_2017, Hansen_2017, Feliubadalo_2017, Bonache_2018, Young_2018, Akcay_2020, Uyisenga_2020, Wang_2020, Bono_2021, Dorling_2021, Krivokuca_2021, Lerner-Ellis_2021, Mio_2021, Singhal_2021). One of these studies reported that segregation analysis of the variant did not support pathogenicity (Hansen_2017). Furthermore, this variant was observed in multiple unaffected controls in a breast cancer case-control study (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. A co-occurrence with a pathogenic variant has been reported (BRIP1 c.2947delA, p.Ile983Leufs*2; Lerner-Ellis_2021). Further co-occurrences with pathogenic variants in other genes were cited by two submitters in ClinVar without providing specific information (SCV001549224.1, SCV000185908.6). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eighteen clinical diagnostic laboratories have submitted clinical-significance assessments for this germline variant to ClinVar after 2014 and classified the variant with conflicting assessments (Benign=1, Likely Benign=2, VUS=15). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121835	SCV000711439	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Asn335Ser variant in PMS2 has been reported in 1 individual who had underg one testing for a personal or family history of breast or ovarian cancer (Caster a 2014) and 1 healthy individual (Bodian 2014). This variant has been identified in 27/65558 (0.04%) European chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP 200513014). Computational prediction tools and conservation analysis suggest that the p.Asn335Ser variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Asn335Ser variant is un certain.
PreventionGenetics, part of Exact Sciences	RCV003389688	SCV000806163	uncertain significance	PMS2-related condition	2023-04-13	criteria provided, single submitter	clinical testing	The PMS2 c.1004A>G variant is predicted to result in the amino acid substitution p.Asn335Ser. This variant has been reported many times in individuals affected with several different types of cancer including breast and/or ovarian cancer, colorectal cancer, pancreatic cancer, and individuals with Lynch syndrome (see for examples Supplementary Table S1 in Castera et al. 2014. PubMed ID: 24549055; Supplementary Table S5 in Maxwell et al. 2016. PubMed ID: 27153395; Rummel et al. 2017. PubMed ID: 28503720; reported as VUS in Huang et al. 2018. PubMed ID: 29625052; Wang et al. 2020. PubMed ID: 31992580). However, a segregation study of individuals with Lynch syndrome did not support pathogenicity for this variant (Hansen et al. 2017. PubMed ID: 28195393). Additionally a case-control study found this variant in several unaffected controls (Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6029571-T-C). This variant has conflicting interpretations in ClinVar, ranging from a variant of uncertain significance to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127751/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mendelics	RCV003492485	SCV001137308	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000415644	SCV001450725	uncertain significance	Lynch syndrome 4	2023-06-22	criteria provided, single submitter	clinical testing	The PMS2 c.1004A>G (p.Asn335Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 28195393, 28874130, 28135145, 29945567, 29684080), breast cancer (PMID: 32959997, 28503720, 28591191, 30306255, 25186627), and other cancers (PMID: 24549055, 29684080). The variant did not segregate with disease in one report (PMID: 28195393). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586586	SCV001472056	uncertain significance	not provided	2021-04-21	criteria provided, single submitter	clinical testing	The PMS2 c.1004A>G; p.Asn335Ser variant (rs200513014) is reported in the literature in individuals with hereditary breast and/or ovarian cancer (Bonache 2018, Castera 2014, Maxwell 2016, Rummel 2017, Young 2018, Tung 2015) and in individuals with Lynch syndrome/colorectal cancer (Hansen 2017, Rossi 2017, Wang 2020, Yurgelun 2017); however, an affected relative did not carry the variant (Hansen 2017). This variant is reported in ClinVar (Variation ID: 127751). It is found in the general population with an allele frequency of 0.03% (77/282,046 alleles). The asparagine at codon 335 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.972). Based on the available information, the clinical significance of this variant is uncertain at this time.
Baylor Genetics	RCV000415644	SCV001481209	uncertain significance	Lynch syndrome 4	2019-09-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000586586	SCV001747499	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798333	SCV002042777	uncertain significance	Breast and/or ovarian cancer	2023-04-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115647	SCV002529744	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121835	SCV002550728	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000586586	SCV003811210	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing
ITMI	RCV000121835	SCV000086033	not provided	not specified	2013-09-19	no assertion provided	reference population
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415644	SCV000493783	uncertain significance	Lynch syndrome 4	2016-03-30	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115647	SCV000788098	uncertain significance	Hereditary cancer-predisposing syndrome	2017-12-08	no assertion criteria provided	clinical testing
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249992	SCV001424006	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354576	SCV001549224	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Asn335Ser variant was identified in 6 of 1000 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, solid tumor, and colorectal cancer (Castera 2014, Hansen 2017, Le 2017, Rummel 2017, Stafford 2017, Rossi 2017). The variant was identified in our laboratory in a patient with a co-occuring pathogenic MLH1 variant suggesting that the PMS2 cp.Asn335Ser variant does not have clinical significance. The variant was also identified in the following databases: dbSNP (ID: rs200513014) as "With Uncertain significance allele", ClinVar (9x uncertain significance by LMM, GeneDx and 7 additional submitters, 1x likely benign by Ambry, and 1x as Benign by Invitae). The variant was identified in control databases in 78 of 276560 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Of note, in the European population, the variant was found in 59 of 126526 chromosomes (freq. 0.0005). The p.Asn335 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.
Genetic Services Laboratory, University of Chicago	RCV000121835	SCV003839888	uncertain significance	not specified	2022-10-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the PMS2 gene demonstrated a sequence change, c.1004A>G, in exon 10 that results in an amino acid change, p.Asn335Ser. This sequence change has been previously described in individuals with breast, ovarian, colorectal and other cancer and solid tumors (PMID: 24549055, 30306255, 31992580, 32522261, 34371384, 32959997, 32658311, 33850299, 28874130, 33821390, 28195393, 32975687). Tumors with this variant have not shown microsatellite instability (PMID: 31391288). This sequence change has been described in the gnomAD database with a frequency of 0.04% in the European subpopulation (dbSNP rs200513014). The p.Asn335Ser change affects a highly conserved amino acid residue located in a domain of the PMS2 protein that is known to be functional. The p.Asn335Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn335Ser change remains unknown at this time.