Submissions for variant NM_024675.4(PALB2):c.1145G>T (p.Ser382Ile)

gnomAD frequency: 0.00001  dbSNP: rs515726063

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114461	SCV000267996	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114461	SCV000488114	uncertain significance	Familial cancer of breast	2015-12-30	criteria provided, single submitter	clinical testing
Invitae	RCV000114461	SCV000550622	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 382 of the PALB2 protein (p.Ser382Ile). This variant is present in population databases (rs515726063, gnomAD 0.004%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 22241545, 26283626, 26315354). ClinVar contains an entry for this variant (Variation ID: 126591). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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.
GeneDx	RCV000483203	SCV000566387	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no damaging effect: HDR activity comparable to wild type (Wiltshire et al., 2019); Observed in individuals with breast/ovarian cancer and also in controls (Tischkowitz et al., 2012; Thompson et al., 2015; Decker et al., 2017); This variant is associated with the following publications: (PMID: 22241545, 28779002, 26283626, 26315354, 31636395)
Ambry Genetics	RCV000567033	SCV000666873	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-19	criteria provided, single submitter	clinical testing	The p.S382I variant (also known as c.1145G>T), located in coding exon 4 of the PALB2 gene, results from a G to T substitution at nucleotide position 1145. The serine at codon 382 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). Across multiple studies, this alteration has been identified in 1/565 women with unilateral breast cancer (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80), in 1/1996 high risk breast cancer patients and 0/1998 unaffected controls (Thompson ER et al. Breast Cancer Res., 2015 Aug;17:111), in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107(11)), in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098), and in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000567033	SCV000685856	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 382 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not affect homology-directed repair activity of the PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 22241545, 26283626) and ovarian cancer (PMID: 26315354). This variant has not shown a significant association with breast cancer in a large case-control study (OR=2.21, 95%CI 0.429 to 11.394, p-value=0.459; PMID: 33471991). This variant has also been identified in 5/282604 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483203	SCV002046954	uncertain significance	not provided	2021-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567033	SCV002530588	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483178	SCV002783100	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-12-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114461	SCV004019754	likely benign	Familial cancer of breast	2023-04-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Leiden Open Variation Database	RCV000114461	SCV001193068	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.