Submissions for variant NM_024675.4(PALB2):c.11C>T (p.Pro4Leu)

gnomAD frequency: 0.00010  dbSNP: rs45619737

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590674	SCV000149972	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: intact interaction with BRCA2 and no decrease in cell survival after exposure to olaparib (Rodrigue et al., 2019); 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: 25801821, 26283626, 23824750, 17200668, 26315354, 26564480, 27878467, 28779002, 31586400, 33471991, 20871615, 19369211, 30303537)
Invitae	RCV000114464	SCV000166639	likely benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116063	SCV000183789	likely benign	Hereditary cancer-predisposing syndrome	2019-01-30	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114464	SCV000267977	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Fulgent Genetics, Fulgent Genetics	RCV000515208	SCV000611496	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Tracheoesophageal fistula	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797625	SCV000699524	likely benign	not specified	2023-09-03	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.11C>T (p.Pro4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.6e-05 in 254736 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.6e-05 vs 0.00016), allowing no conclusion about variant significance. c.11C>T has been reported in the literature in individuals affected with breast cancer, epithelial ovarian cancer and in controls (Damiola_2015, Rahman_2007, Ramus_2015, Thompson_2015, Yadav_2015, Girard_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Rodrigue_2019). These results showed no damaging effect of this variant on ability to interact with BRCA1 and sensitivity to PARP inhibition. The following publications have been ascertained in the context of this evaluation (PMID: 26564480, 30303537, 17200668, 26315354, 31586400, 26283626, 23824750, 27878467). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as variant of uncertain significance (n=8) and likely Benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000590674	SCV000807070	uncertain significance	not provided	2017-11-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116063	SCV000902662	likely benign	Hereditary cancer-predisposing syndrome	2015-09-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798292	SCV002043581	uncertain significance	Breast and/or ovarian cancer	2019-06-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590674	SCV002047219	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00028 (14/49362 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 27878467 (2016), 26564480 (2015), 26283626 (2015), 23824750 (2014)) and ovarian cancer (PMID: 26315354 (2015). It has also been reported in unaffected individuals (PMID: 33471991 (2021), 30303537 (2019), 26564480 (2015), 26315354 (2015)). This variant has also been shown to have no effect on BRCA1 binding and sensitivity to PARP1 inhibitor (PMID: 31586400 (2019)), however further studies are required to determine this variant’s effect on PALB2 protein function. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000116063	SCV002530594	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590674	SCV004702164	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	PALB2: PM2, BP4
Leiden Open Variation Database	RCV000114464	SCV001192898	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358373	SCV001554087	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Pro4Leu variant was identified in 8 of 14674 proband chromosomes (frequency: 0.0006) from individuals or families with breast or ovarian cancer and was present in 5 of 14350 control chromosomes (frequency: 0.0003) from healthy individuals (Damiola 2015, Ramus 2015, Thompson 2015, Wong-Brown 2014, Rahman 2007). The variant was also identified in dbSNP (ID: rs45619737) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Genedx, Invitae and five other submitters), and in LOVD 3.0 (1x). The variant was identified in control databases in 19 of 273268 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 23580 chromosomes (freq: 0.000127), European in 16 of 124140 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Pro4 residue is not conserved in mammals and four out of five 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) 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. This variant is classified as a variant of uncertain significance.