Submissions for variant NM_000535.7(PMS2):c.163+4A>G

gnomAD frequency: 0.00001  dbSNP: rs864622749

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205498	SCV000262291	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 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 not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 221108). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Counsyl	RCV000409621	SCV000488510	uncertain significance	Lynch syndrome 4	2016-04-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580174	SCV000686147	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +4 position of intron 2 of the PMS2 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has not been identified 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.
GeneDx	RCV001589096	SCV001823289	uncertain significance	not provided	2019-12-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals undergoing multi-gene panel testing for a Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754)
Sema4, Sema4	RCV000580174	SCV002530210	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	curation
Ambry Genetics	RCV000580174	SCV002704459	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	The c.163+4A>G intronic variant results from an A to G substitution 4 nucleotides after coding exon 2 in the PMS2 gene. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000409621	SCV004019827	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	RCV000409621	SCV004205435	uncertain significance	Lynch syndrome 4	2023-09-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997669	SCV004824795	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +4 position of intron 2 of the PMS2 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has not been identified 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.