Submissions for variant NM_000535.7(PMS2):c.803+4A>G

gnomAD frequency: 0.00001  dbSNP: rs756312205

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566972	SCV000670763	likely benign	Hereditary cancer-predisposing syndrome	2024-10-07	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	RCV000566972	SCV000686241	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-05	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +4 position of intron 7 of the PMS2 gene. Splice site prediction tools are inconclusive on whether this variant has a significant impact on RNA splicing. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/248408 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.
GeneKor MSA	RCV000566972	SCV000822137	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818231	SCV000958832	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the PMS2 gene. It does not directly change the encoded amino acid sequence of the PMS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756312205, gnomAD 0.0009%). This variant has been observed in individual(s) with prostate cancer and/or personal or family history of hereditary breast and/or ovarian cancer (PMID: 29368341, 31159747). ClinVar contains an entry for this variant (Variation ID: 484256). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in Invitae (multiple RNA products). 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.
Sema4, Sema4	RCV000566972	SCV002530391	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000292	SCV005625933	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	The PMS2 c.803+4A>G variant has been reported in the published literature in individuals with prostate cancer (PMID: 29368341 (2018)) and personal and/or family history of breast and/or ovarian cancer (PMID: 31159747 (2019)). The frequency of this variant in the general population, 0.0000081 (2/248408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PMS2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.