Submissions for variant NM_024675.4(PALB2):c.212-2A>G

gnomAD frequency: 0.00002  dbSNP: rs730881879

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160830	SCV000211503	likely pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); A different variant at this splice site is reported to cause aberrant splicing leading to skipping of exons 4 and 5, which is predicted to result in a null allele (Lopez-Perolio et al., 2019); This variant is associated with the following publications: (PMID: 31589614, 30293905, 32172797, 35626031, 26681312, 30890586)
Invitae	RCV000206312	SCV000261091	pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881879, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182757). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30890586; Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000213220	SCV000277096	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The c.212-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the PALB2 gene. This alteration has been identified in multiple individuals with a personal history of breast and/or ovarian cancer (Susswein LR et al. Genet. Med. 2016 08;18:823-32; Espinel W et al. Cancers (Basel), 2022 May;14:). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213220	SCV000537626	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -2 position of intron 3 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A minigene splicing assay reported that a similar canonical splice acceptor site variant in intron 3, c.212-1G>A, resulted in the out-of-frame skipping of exon 4 and exon 5 (PMID: 30890586). This variant has been reported in an individual affected with breast cancer (PMID: 26681312). This variant has been identified in 1/221342 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Counsyl	RCV000206312	SCV000677809	likely pathogenic	Familial cancer of breast	2015-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206312	SCV000919928	likely pathogenic	Familial cancer of breast	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.212-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 217494 control chromosomes. c.212-2A>G has been reported in the literature in one individual affected with Breast Cancer (Susswein_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000206312	SCV001481177	pathogenic	Familial cancer of breast	2023-12-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781505	SCV002016512	pathogenic	Fanconi anemia complementation group N	2019-02-10	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000160830	SCV002502673	likely pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160830	SCV002774369	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	This test has identified one copy of the c.212-2A>G variant in the PALB2 gene. This variant is located in a canonical splice-acceptor site and interferes with normal PALB2 mRNA splicing. The variant has been reported in an individual with breast cancer in the published literature (PMID: 26681312 (2015)). Based on the available information, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498799	SCV002811628	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-08-05	criteria provided, single submitter	clinical testing