Submissions for variant NM_024675.4(PALB2):c.2612A>G (p.Asp871Gly)

gnomAD frequency: 0.00002  dbSNP: rs515726090

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114547	SCV000550628	uncertain significance	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 871 of the PALB2 protein (p.Asp871Gly). This variant is present in population databases (rs515726090, gnomAD 0.006%). This missense change has been observed in individual(s) with breast, pancreatic and colorectal cancer (PMID: 22692731, 25452441, 32658311, 32885271, 33980423, 34371384). ClinVar contains an entry for this variant (Variation ID: 126670). 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 have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395, 31757951). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000522335	SCV000617241	uncertain significance	not provided	2022-06-08	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; In silico analysis supports a deleterious effect on splicing; Observed in individuals with breast and/or ovarian cancer (Catucci 2012, Couch 2015); Published functional studies demonstrate homology-directed repair (HDR) activity, protein stability, and maintenance of the G2/M checkpoint similar to wild type (Boonen 2019, Wiltshire 2020); This variant is associated with the following publications: (PMID: 25452441, 22692731, 19609323, 20871615, 24485656, 31757951, 31636395)
Ambry Genetics	RCV000572146	SCV000663313	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.D871G variant (also known as c.2612A>G), located in coding exon 7 of the PALB2 gene, results from an A to G substitution at nucleotide position 2612. The aspartic acid at codon 871 is replaced by glycine, an amino acid with similar properties. This alteration was detected in a cohort of 1824 patients with triple negative breast cancer who were unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11), in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879) and in 1/189 colorectal cancer patients and in none of the cancer-free elderly controls in a Turkish population(Akcay IM et al. Int J Cancer. 2021 01;148(2):285-295). This alteration was also reported in an Ashkenazi Jewish female diagnosed with breast cancer at age 50; her mother, two maternal aunts, and maternal grandmother were also diagnosed with breast cancer. The alteration was not detected in 113 Ashkenazi cancer-free controls (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91). 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). This alteration was also evaluated in another functional study, and was found to be functionally normal in a homology-directed DNA repair (HDR) assay, and in a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 11;10:5296). 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.
Color Diagnostics, LLC DBA Color Health	RCV000572146	SCV000685964	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 871 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant has no impact on PALB2 function in homology-directed repair, checkpoint response and sensitivity to cisplatin and PARP inhibitors assays (PMID: 31636395, 31757951). This variant has been reported in individuals affected with breast cancer and unaffected individuals, and it also has been reported in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 22692731, 25452441, 32885271, 33471991, 33980423; Leiden Open Variation Database DB-ID PALB2_010115). This variant also has been reported in an individual affected with pancreatic cancer (PMID: 34371384). This variant has been identified in 4/251488 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.
Counsyl	RCV000114547	SCV000785155	uncertain significance	Familial cancer of breast	2017-05-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572146	SCV002530712	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490765	SCV002776923	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114547	SCV004019683	uncertain significance	Familial cancer of breast	2023-03-31	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	RCV000114547	SCV004202096	uncertain significance	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114547	SCV001193264	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	RCV001356501	SCV001551692	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Asp871Gly variant was identified in 2 of 3840 proband chromosomes (frequency: 0.0005) from individuals or families with breast cancer and was not identified in 226 control chromosomes from healthy individuals (Catucci 2012, Couch 2015). The variant was also identified in dbSNP (ID: rs515726090), ClinVar (classified as uncertain significance by Invitae, PALB2 database), Clinvitae (classified as uncertain significance by Invitae), LOVD 3.0 (2X), databases. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 4 of 246266 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European Non-Finnish in 2 of 111718 chromosomes (freq: 0.000018), and SouthAsian in 2 of 30782 chromosomes (freq: 0.000065); it was not observed in the African, “Other”, Latino, AshkenaziJewish, EastAsian, EuropeanFinnish, populations. The p.Asp871 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.