Submissions for variant NM_024675.4(PALB2):c.721A>G (p.Asn241Asp)

gnomAD frequency: 0.00202  dbSNP: rs113217267

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV001083216	SCV003915574	benign	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.721A>G variant in PALB2 is a missense variant predicted to predicted to cause substitution of asparagine by aspartic acid at amino acid 241 (p.Asn241Asp). This variant has been observed in three homozygous individuals with no features of FANCN, a condition with full penetrance at an early age (Ambry Genetics). The highest population minor filtering allele frequency in gnomAD v2.1.1 is 0.005509 in the African population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (BA1, BS2, BP1)
GeneDx	RCV000121748	SCV000150020	likely benign	not specified	2018-01-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000116111	SCV000172927	benign	Hereditary cancer-predisposing syndrome	2018-11-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV001083216	SCV000252866	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121748	SCV000596216	likely benign	not specified	2017-04-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116111	SCV000686072	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587175	SCV000699611	benign	not provided	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.721A>G (p.Asn241Asp) variant involves the alteration of a non-conserved nucleotide and 5/5 in silico tools predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 75/121762 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006935 (71/10238). This frequency is about 44 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications have cited the variant in affected individuals, predominantly of African decent, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000587175	SCV000807116	likely benign	not provided	2016-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587175	SCV000888384	benign	not provided	2022-07-07	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225311	SCV002504941	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116111	SCV002531214	benign	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315624	SCV004016503	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492445	SCV004239564	likely benign	Breast and/or ovarian cancer	2022-10-28	criteria provided, single submitter	clinical testing
ITMI	RCV000121748	SCV000085946	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV000587175	SCV001193006	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356373	SCV001551523	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Asn241Asp variant was identified in 13 of 2290 proband chromosomes (frequency: 0.00567) from individuals or families with breast cancer (Ding 2011, Zhen 2015, Zheng 2012). The variant was also identified in dbSNP (ID: rs113217267) as With Uncertain significance, other allele, ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx, Ambry Genetics, PALB2 database), Clinvitae (classified as benign by Invitae; classified as likely benign by ClinVar), MutDB, LOVD 3.0 (5X), Zhejiang Colon Cancer Database (1X), databases. The variant was not identified in Cosmic, database. The variant was identified in control databases in 167(2 homozygous) of 277184 chromosomes at a frequency of 0.000602 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asn241 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121748	SCV001807032	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587175	SCV001958905	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587175	SCV001977623	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587175	SCV002035774	likely benign	not provided		no assertion criteria provided	clinical testing