Submissions for variant NM_024675.4(PALB2):c.3128G>C (p.Gly1043Ala)

gnomAD frequency: 0.00001  dbSNP: rs377713277

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131630	SCV000186653	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-09	criteria provided, single submitter	clinical testing	The p.G1043A variant (also known as c.3128G>C), located in coding exon 11 of the PALB2 gene, results from a G to C substitution at nucleotide position 3128. The glycine at codon 1043 is replaced by alanine, an amino acid with similar properties. This variant is located in the carboxy-terminal WD40-repeat motif of the PALB2 protein, near the region where BRCA2 binds across a hydrophobic pocket of PALB2 (codons 1053–1057) (Oliver AW et al. EMBO Rep. 2009 Sep; 10(9):990-6; Hofstatter EW et al. Fam Cancer. 2011 Jun; 10(2):225-31). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22:622-632). Whereas another group performed multiple functional studies and demonstrated that this alteration leads to intermediate functional defects; specifically, this alteration was found to have an intermediate recombination defect with reduced HDR activity of 50% compared to the wildtype control, despite normal nuclear localization and modest decrease of RAD51 foci (Rodrigue A et al. Nucleic Acids Res. 2019 11;47:10662-10677). This alteration has been reported in multiple cohorts of patients with a personal and/or family history of breast and/or ovarian cancer; however, this alteration was also identified in healthy controls (Hofstatter EW et al. Fam Cancer. 2011 Jun; 10(2):225-31; Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111; Damiola F et al. Breast Cancer Res. Treat. 2015 Dec;154(3):463-71; Kanchi KL et al. Nat Commun. 2014;5:3156; Dorling et al. N Engl J Med, 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879; Gonzalez A et al, Breast Cancer Res Treat 2022 Jul;194(2):403-412). This variant did not co-segregate with disease in one breast cancer family reported in published literature; this family had two sisters affected with breast cancer and only one carried the variant (Hellebrand H et al. 2011. Hum Mutat. 2011 Jun;32(6):E2176-88). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114598	SCV000268023	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000131630	SCV000537611	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 1043 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). Functional studies have shown that this variant has partially reduced to near full PALB2 activities compared to wild-type in homology-directed repair assays (PMID: 31636395, 31586400), and partial loss-of-function in subcellular localization and PARP inhibitor sensitivity assays (PMID: 31586400). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21365267, 21618343, 25186627, 26283626, 26315354). This variant has also been reported in breast and ovarian cancer case-control studies in unaffected individuals but absent in cases (PMID: 26564480, 30303537, 33471991; Leiden Open Variation Database DB-ID PALB2_010151). This variant has been identified in 4/250794 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.
Invitae	RCV000114598	SCV000550620	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1043 of the PALB2 protein (p.Gly1043Ala). This variant is present in population databases (rs377713277, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 21365267, 21618343, 26283626, 26315354, 26564480). ClinVar contains an entry for this variant (Variation ID: 126716). 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 expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31586400, 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	RCV000485289	SCV000566840	uncertain significance	not provided	2023-06-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26564480, 26315354, 21365267, 21618343, 25186627, 26283626, 31586400, 31636395, 33195396, 33471991, 30303537, 31422574, 24448499)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780560	SCV000917938	uncertain significance	not specified	2021-08-20	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3128G>C (p.Gly1043Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 263364 control chromosomes. c.3128G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (examples- Hellebrand_2011, Hofstatter_2011, Tung_2014, Ramus_2015, Thompson_2015), but also in controls (examples- Kanchi_2014, Damiola_2015, Girard_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function, reporting conflicting results. In one study, the variant was reported to have no significant effect on homology-directed repair (HDR) activity (Wiltshire_2019), but in another study modest reductions in HDR activity were observed, and the variant protein was shown to exhibit reduced interaction with BRCA2 in a mammalian two hybrid assay (Rodrigue_2019). Seven other 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000131630	SCV001424031	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-30	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>C) that results in a glycine to alanine amino acid change at residue 1043 in the PALB2 protein. This is a previously reported (ClinVar, HGMD), rare variant in control population datasets (gnomAD database, 5/245648 alleles, 0.002% overall frequency) that has also been observed in multiple breast and ovarian cancer patients (PMIDs 21365267, 21618343, 26283626, 26315354). The Gly1043 residue is located within the functional domain of PALB2 necessary for its interaction with BRCA2 (PMIDs 24485656, 17200672), but functional studies have not been performed to determine if this interaction is disrupted in the presence of this variant. Multiple bioinformatic tools queried are in agreement that this amino acid change would be damaging, and the Gly1043 residue is completely evolutionarily conserved across more than 50 mammalian species examined. At this time, there is not enough evidence to determine whether this variant is pathogenic or benign; thus, it is a variant of uncertain significance.
Sema4, Sema4	RCV000131630	SCV002530756	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-14	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483180	SCV002788182	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114598	SCV004201990	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114598	SCV001193358	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	RCV000485289	SCV001550164	uncertain significance	not provided		no assertion criteria provided	clinical testing	PALB2, EXON11, c.3128G>C, p.Gly1043Ala, Heterozygous, Uncertain Significance The PALB2 p.Gly1043Ala variant was identified in 5 of 16464 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer and was present in 1 of 1324 control chromosomes (frequency: 0.0008) from healthy individuals (Damiola 2015, Hellebrand 2011, Hofstatter 2011, Ramus 2015, Thompson 2015, Tung 2015). The variant was also identified in the following databases: dbSNP (ID: rs377713277) as "With Uncertain significance allele", ClinVar (6x uncertain significance), Clinvitae, and LOVD 3.0 (4x). The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 245648 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 5 of 111408 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly1043 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the c.3128G>C variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.