Submissions for variant NM_024675.4(PALB2):c.1699C>T (p.His567Tyr)

gnomAD frequency: 0.00004  dbSNP: rs370422990

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588850	SCV000149981	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, as well as unaffected controls (Tischkowitz et al., 2012; Tung et al., 2015; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 25186627, 22241545, 26283626, 26315354, 31843900, 33471991)
Ambry Genetics	RCV000116072	SCV000186670	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.H567Y variant (also known as c.1699C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 1699. The histidine at codon 567 is replaced by tyrosine, an amino acid with similar properties. This alteration was detected in 1/565 unilateral breast cancer patients, but not in 559 bilateral breast cancer patients (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). In another study, this variant was not detected in a total of 1995 breast cancer cases, but was detected in 1/1998 healthy controls (Thompson ER et al. Breast Cancer Res. 2015 Aug;17:111). In another study, this alteration was observed in 0/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:). This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114495	SCV000219076	benign	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114495	SCV000268004	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000116072	SCV000537519	likely benign	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171429	SCV000699543	likely benign	not specified	2022-08-19	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1699C>T (p.His567Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 254898 control chromosomes, predominantly at a frequency of 0.001 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1699C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome as well as in controls (Tischkowitz_2012, Thompson_2015, Ramus_2015, Tung_2015, Dorling_2021, Delahunty_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV001292820	SCV001481490	uncertain significance	Fanconi anemia complementation group N	2019-01-20	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000588850	SCV002063502	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116072	SCV002530639	likely benign	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116072	SCV004014938	likely benign	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001171429	SCV004027082	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588850	SCV004222271	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast and/or ovarian cancer (PMIDs: 22241545 (2012), 25186627 (2015), 33471991 (2021) see also LOVD (http://databases.lovd.nl/PALB2), 35263119 (2022)) and in healthy individuals (PMIDs: 26283626 (2015), 26315354 (2015), 33471991 (2021) see also LOVD (http://databases.lovd.nl/PALB2)). The frequency of this variant in the general population, 0.001 (10/9914 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
True Health Diagnostics	RCV000116072	SCV000788087	uncertain significance	Hereditary cancer-predisposing syndrome	2017-08-04	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000114495	SCV001193149	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
King Laboratory, University of Washington	RCV001171429	SCV001251338	benign	not specified	2019-09-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004529918	SCV004744523	uncertain significance	PALB2-related disorder	2023-12-12	no assertion criteria provided	clinical testing	The PALB2 c.1699C>T variant is predicted to result in the amino acid substitution p.His567Tyr. This variant has been reported in several individuals with breast cancer (Tischkowitz et al. 2012. PubMed ID: 22241545; Tung et al. 2015. PubMed ID: 25186627; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991), but it has also been documented in multiple unaffected individuals in several large breast/ovarian cancer case-control studies (Thompson et al. 2015. PubMed ID: 26283626; Ramus et al. 2015. PubMed ID: 26315354; Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.10% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126622). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence.