Submissions for variant NM_024675.4(PALB2):c.1756G>A (p.Asp586Asn)

gnomAD frequency: 0.00003  dbSNP: rs587781954

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130326	SCV000185176	likely benign	Hereditary cancer-predisposing syndrome	2024-03-13	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.
Counsyl	RCV000411835	SCV000488987	uncertain significance	Familial cancer of breast	2016-07-29	criteria provided, single submitter	clinical testing
Invitae	RCV000411835	SCV000550647	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 586 of the PALB2 protein (p.Asp586Asn). This variant is present in population databases (rs587781954, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141709). 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 not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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	RCV000481375	SCV000565350	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with breast cancer (PMID: 25186627); This variant is associated with the following publications: (PMID: 25186627)
Fulgent Genetics, Fulgent Genetics	RCV000764051	SCV000895005	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130326	SCV000903125	likely benign	Hereditary cancer-predisposing syndrome	2015-06-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798444	SCV002043587	uncertain significance	Breast and/or ovarian cancer	2020-03-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411835	SCV004019650	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. 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. 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].
Baylor Genetics	RCV000411835	SCV004202119	uncertain significance	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000411835	SCV001193152	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.