Submissions for variant NM_024675.4(PALB2):c.1222T>C (p.Tyr408His)

dbSNP: rs515726064

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000802122	SCV000941938	uncertain significance	Familial cancer of breast	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 408 of the PALB2 protein (p.Tyr408His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and PALB2-related conditions (PMID: 21365267, 32522261). ClinVar contains an entry for this variant (Variation ID: 126594). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 29387807, 31636395, 31757951). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000802122	SCV001449480	uncertain significance	Familial cancer of breast	2020-11-20	criteria provided, single submitter	clinical testing	PALB2 c.1222T>C has been reported in an individual with a personal history of breast cancer. It is located within the chromatin association motif (ChAM). This variant is absent from a large population dataset and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, and the tyrosine residue at this position is highly evolutionarily conserved across all species assessed. We consider the clinical significance of c.1222T>C to be uncertain at this time.
GeneDx	RCV001355987	SCV002005057	uncertain significance	not provided	2020-12-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: homology directed repair activity, cisplatin sensitivity, PARP inhibitor sensitivity, and ChAM-mediated chromatin localization all comparable to wild-type (Bleuyard 2017, Boonen 2019, Wiltshire 2019); Observed in an individual with a personal history of breast cancer in published literature (Hofstatter 2011); This variant is associated with the following publications: (PMID: 21365267, 31757951, 29387807, 31636395)
Ambry Genetics	RCV003362687	SCV004057626	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	The p.Y408H variant (also known as c.1222T>C), located in coding exon 4 of the PALB2 gene, results from a T to C substitution at nucleotide position 1222. The tyrosine at codon 408 is replaced by histidine, an amino acid with similar properties. This alteration has been detected in multiple hereditary breast/ovarian cancer (HBOC) cohorts (Hofstatter EW et al. Fam Cancer, 2011 Jun;10:225-31; Velázquez C et al. J Transl Med, 2020 Jun;18:232; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Gonzalez A et al. Breast Cancer Res Treat, 2022 Jul;194:403-412). This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay, a RAD51 foci assay, and in a PARP inhibitor sensitivity assay (Boonen RACM et al. Nat Commun, 2019 Nov;10:5296). This alteration was found to be functionally normal in another homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 Mar;22:622-632). 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.
Leiden Open Variation Database	RCV001030206	SCV001193075	uncertain significance	Pancreatic cancer, susceptibility to, 3	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	RCV001355987	SCV001551031	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Tyr408His variant was was identified in 1 of 188 proband chromosomes (frequency: 0.005) from BRCA1/2-negative individuals or families with a personal and/or family history of pancreatic cancer (Hofstatter 2011). The variant was not identified in dbSNP, Cosmic, MutDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium control databases (August 8th 2016). The variant was identified in ClinVar (classified as uncertain significance by PALB2 database) and LOVD 3.0 database (1x). The p.Tyr408 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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