Submissions for variant NM_024675.4(PALB2):c.1697G>A (p.Arg566His)

gnomAD frequency: 0.00001  dbSNP: rs144617793

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116071	SCV000149980	uncertain significance	not provided	2017-05-17	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.1697G>A at the cDNA level, p.Arg566His (R566H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a colon adenocarcinoma (Seshagiri 2012). PALB2 Arg566His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. PALB2 Arg566His occurs at a position that is not conserved and is located in the DNA-binding domain (Uniprot). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PALB2 Arg566His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000229982	SCV000290815	uncertain significance	Familial cancer of breast	2022-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 566 of the PALB2 protein (p.Arg566His). This variant is present in population databases (rs144617793, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 128122). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000564017	SCV000663303	likely benign	Hereditary cancer-predisposing syndrome	2018-02-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000564017	SCV000911951	likely benign	Hereditary cancer-predisposing syndrome	2019-10-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000116071	SCV001134539	uncertain significance	not provided	2020-11-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564017	SCV002530638	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001030254	SCV002551672	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001030254	SCV004021216	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1697G>A (p.Arg566His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 400498 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (2.5e-05 vs 0.00016), allowing no conclusion about variant significance. c.1697G>A has been reported in the literature in individuals affected with breast cancer without strong evidence of causality, as well as unaffected controls (Momozawa_2018, Dorling_2021, Fujita_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. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 33309985, 33471991). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified it as benign/likely benign (n=3) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004542828	SCV004773598	uncertain significance	PALB2-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	The PALB2 c.1697G>A variant is predicted to result in the amino acid substitution p.Arg566His. This variant was reported in an individual with breast cancer from a large Japanese cohort (Momozawa et al. 2018. PubMed ID: 30287823). Another large case-control study detected this variant in four individuals with breast cancer but also in two unaffected controls (Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant is reported in 0.0066% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128122/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV001030254	SCV001193147	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000116071	SCV001906296	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000116071	SCV001932592	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116071	SCV001953948	likely benign	not provided		no assertion criteria provided	clinical testing