Submissions for variant NM_024675.4(PALB2):c.1492G>T (p.Asp498Tyr)

gnomAD frequency: 0.00020  dbSNP: rs75023630

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000858743	SCV000211557	likely benign	not provided	2021-06-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26411315, 28580595, 23977390, 25186627, 26283626, 26692951, 23555315, 27783279, 28796317, 28825143, 30309218, 28767289, 29338689, 31757951)
Ambry Genetics	RCV000160870	SCV000215553	benign	Hereditary cancer-predisposing syndrome	2014-12-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197379	SCV000253582	benign	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000197379	SCV000268000	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000160870	SCV000396111	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000368837	SCV000396112	likely benign	Fanconi anemia complementation group N	2018-01-13	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858743	SCV000601730	likely benign	not provided	2019-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160870	SCV000685885	likely benign	Hereditary cancer-predisposing syndrome	2015-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200991	SCV000917958	benign	not specified	2021-01-09	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1492G>T (p.Asp498Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251452 control chromosomes, predominantly at a frequency of 0.0059 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 38 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 East Asian origin. c.1492G>T has been reported in the literature as a non-specific variant in individuals affected with a variety of cancers (example, Nakagomi_2015, Phuah_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (APC c.3184_3187delCAAA, p.Gln1062ValfsX63), providing additional supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus of likely benign (n=6)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030650	SCV001193681	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000160870	SCV002530618	benign	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Leiden Open Variation Database	RCV000858743	SCV001193114	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	RCV001356483	SCV001551666	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Asp498Tyr variant was identified in 133 of 21516 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer and was present in 397 of 51832 control chromosomes (frequency: 0.008) from healthy individuals (Momozawa 2018, Phuah 2013, Rashid 2018, Tung 2015). The variant was also identified in dbSNP (ID: rs75023630) as "With Uncertain significance, other allele", ClinVar (classified as benign by Invitae and Ambry Genetics; as likely benign by four submitters; as uncertain significance by two submitters), and LOVD 3.0 (6x as benign or likely benign). The variant was identified in control databases in 131 of 277200 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6462 chromosomes (freq: 0.0002), East Asian in 118 of 18868 chromosomes (freq: 0.006), and South Asian in 12 of 30782 chromosomes (freq: 0.0004), while the variant was not observed in the African, Latino, European, Ashkenazi Jewish, and Finnish, populations. The p.Asp498 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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) predict 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.