Submissions for variant NM_024675.4(PALB2):c.1955G>A (p.Ser652Asn)

gnomAD frequency: 0.00002  dbSNP: rs587781818

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130094	SCV000184923	likely benign	Hereditary cancer-predisposing syndrome	2018-03-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226926	SCV000290820	likely benign	Familial cancer of breast	2024-12-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000302799	SCV000396105	uncertain significance	Fanconi anemia complementation group N	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000130094	SCV000396106	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000226926	SCV000487972	uncertain significance	Familial cancer of breast	2015-12-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130094	SCV000903094	likely benign	Hereditary cancer-predisposing syndrome	2017-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000842453	SCV000984475	likely benign	not provided	2020-11-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28664506, 25256751, 28825143, 28580595, 30287823, 32566746)
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030649	SCV001193680	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000226926	SCV004019705	uncertain significance	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000842453	SCV005623185	uncertain significance	not provided	2024-03-06	criteria provided, single submitter	clinical testing	The PALB2 c.1955G>A (p.Ser652Asn) variant has been reported in the published literature in individuals affected with breast cancer (PMID: 28664506 (2017), 28580595 (2018), 28825143 (2017), 30287823 (2018), 33471991 (2021), https://databases.lovd.nl/shared/variants/PALB2) and non-small cell lung cancer (PMID: 35087742 (2021)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/PALB2)). The frequency of this variant in the general population, 0.0012 (18/14424 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV001030271	SCV001193173	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358211	SCV001553884	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PALB2 p.Ser652Asn variant was identified in 7 of 4558 proband chromosomes (frequency: 0.0015) from individuals or families with breast cancer (Zhang 2017). The variant was also identified in dbSNP (ID: rs587781818) as "With other allele" and ClinVar (classified as likely benign by Ambry Genetics and Invitae and classified as uncertain significance by Counsyl). The variant was not identified in Cosmic, LOVD 3.0, or the Zhejiang University Database. The variant was identified in control databases in 23 of 277170 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 22 of 18870 chromosomes (freq: 0.001) and Other in 1 of 6468 chromosomes (freq: 0.00015), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Ser652 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.