Submissions for variant NM_000535.7(PMS2):c.379G>A (p.Ala127Thr)

gnomAD frequency: 0.00010  dbSNP: rs114090343

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121857	SCV000171046	benign	not specified	2014-06-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000129112	SCV000183825	likely benign	Hereditary cancer-predisposing syndrome	2018-11-09	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	RCV001084398	SCV000218861	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095167	SCV000469740	likely benign	Lynch syndrome 4	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetic Services Laboratory, University of Chicago	RCV000121857	SCV000596472	likely benign	not specified	2016-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129112	SCV000686198	likely benign	Hereditary cancer-predisposing syndrome	2015-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590269	SCV000697366	likely benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000168196	SCV000887462	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	PMS2 NM_000535.5:c.379G>A has a 70.8% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 1.56 and 1.56 to 1, generated from evidence of seeing this as a somatic mutation in two independent tumors without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590269	SCV000889626	benign	not provided	2022-08-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000121857	SCV001160411	likely benign	not specified	2019-03-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129112	SCV002530337	benign	Hereditary cancer-predisposing syndrome	2020-12-28	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003945100	SCV004756988	likely benign	PMS2-related disorder	2020-04-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
ITMI	RCV000121857	SCV000086059	not provided	not specified	2013-09-19	no assertion provided	reference population
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093698	SCV001250882	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590269	SCV001550059	likely benign	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Ala127Thr variant was not identified in the literature nor was it identified in the following databases: the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant, Zhejiang Colon Cancer, Mismatch Repair Genes Variant, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs114090343); in ClinVar and Clinvitae databases as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, Genetic Services laboratory, University of Chicago; and uncertain significance by Illumina Clinical Services. The variant was identified in control databases in 119 of 276900 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). Observation by population include: “other” in 1 of 6460 chromosomes (freq: 0.0002), European Non-Finnish in 3 of 126390 chromosomes (freq: 0.00002), East Asian in 109 of 18868 chromosomes (freq: 0.005777), and South Asian in 6 of 30782 chromosomes (freq: 0.000195). The variant was not observed in the African, Latino, Ashkenazi Jewish, European Finnish, populations. It was observed in homozygous form in an individual from our lab without features of biallelic mismatch repair syndrome increasing the likelihood this variant is benign. The p.Ala127Thr residue is not conserved in mammals and 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 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.