ClinVar Miner

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

gnomAD frequency: 0.00202  dbSNP: rs113217267
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Other strong data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Subpopulation frequency in support of benign classification
Invitae RCV001083216 SCV000252866 benign Familial cancer of breast 2021-12-17 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121748 SCV000601795 likely benign not specified 2017-02-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116111 SCV000686072 likely benign Hereditary cancer-predisposing syndrome 2014-11-25 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,PreventionGenetics 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 2018-05-22 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
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

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