Submissions for variant NM_024675.4(PALB2):c.3257G>A (p.Arg1086Gln)

gnomAD frequency: 0.00013  dbSNP: rs146377793

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130835	SCV000185733	likely benign	Hereditary cancer-predisposing syndrome	2018-08-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV000590502	SCV000211532	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Case control studies suggest this variant is not significantly associated with breast or prostate cancer (Haiman et al., 2013); Observed in individuals with breast or endometrial cancer (Ring et al., 2016; Momozawa et al., 2018; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 27443514, 30287823, 33309985, 23555315, 35264596, 33471991, 24485656, 19609323, 20871615, 32980694)
Invitae	RCV000203792	SCV000260216	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1086 of the PALB2 protein (p.Arg1086Gln). This variant is present in population databases (rs146377793, gnomAD 0.05%). This missense change has been observed in individual(s) with endometrial cancer and breast cancer (PMID: 27443514, 30287823, 35264596). ClinVar contains an entry for this variant (Variation ID: 142035). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855603	SCV000699587	likely benign	not specified	2022-09-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3257G>A (p.Arg1086Gln) results in a conservative amino acid change located in the Partner and localizer of BRCA2, WD40 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 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 African or African-American origin. The variant was also reported in 4/2559 African American women (i.e. with an allele frequency of 0.0008), who were older than 70 years and have never had cancer (in the FLOSSIES database). These data suggest that the variant is likely a benign polymorphism found primarily in populations of African origin. c.3257G>A has been reported in the literature in individuals affected with breast cancer or endometrial carcinoma, however the variant was indicated to not be significantly associated with an increased cancer risk (examples: Haiman 2013, and Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=8) and benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000203792	SCV000784893	uncertain significance	Familial cancer of breast	2017-01-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000130835	SCV000838998	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590502	SCV000888373	uncertain significance	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130835	SCV000910909	likely benign	Hereditary cancer-predisposing syndrome	2016-05-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000203792	SCV001139984	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000855603	SCV002070738	uncertain significance	not specified	2019-10-08	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225436	SCV002504916	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130835	SCV002531156	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000203792	SCV003807453	uncertain significance	Familial cancer of breast	2022-08-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4 supporting
Myriad Genetics, Inc.	RCV000203792	SCV004019673	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Leiden Open Variation Database	RCV000855603	SCV001193380	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.