Submissions for variant NM_024675.4(PALB2):c.2794G>A (p.Val932Met)

gnomAD frequency: 0.00449  dbSNP: rs45624036

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121760	SCV000149999	benign	not specified	2016-10-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114559	SCV000153851	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116090	SCV000172810	benign	Hereditary cancer-predisposing syndrome	2014-08-05	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114559	SCV000268018	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
PreventionGenetics, part of Exact Sciences	RCV000121760	SCV000314374	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000116090	SCV000396087	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116090	SCV000576428	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000514905	SCV000604595	benign	not provided	2023-11-11	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514905	SCV000609868	likely benign	not provided	2017-02-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116090	SCV000685979	benign	Hereditary cancer-predisposing syndrome	2014-11-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121760	SCV000860262	benign	not specified	2018-04-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000114559	SCV001139997	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514905	SCV001150777	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PALB2: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001118197	SCV001276463	likely benign	Fanconi anemia complementation group N	2018-03-06	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.
Sema4, Sema4	RCV000116090	SCV002530723	benign	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121760	SCV002551649	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498482	SCV002808938	benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149785	SCV003838082	benign	Breast and/or ovarian cancer	2022-03-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315620	SCV004016498	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000514905	SCV005213519	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000121760	SCV000085958	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114559	SCV000207344	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000116090	SCV000788093	likely benign	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000514905	SCV001193291	likely benign	not provided	2019-09-18	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Carlos Vaccaro, Marc Tischkowitz, Melissa DeRycke.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356378	SCV001551530	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357367	SCV001552823	benign	Familial ovarian cancer		no assertion criteria provided	clinical testing	The PALB2 p.Val932Met variant was identified in 60 of 9444 proband chromosomes (frequency: 0.006) from individuals or families with breast, ovarian and prostate cancer and was present in 69 of 12422 control chromosomes (frequency: 0.006) from healthy individuals (Thompson_2015_26283626, Rahman_2007_17200668, Erkko_2007_17287723, Bogdanova_2011_21165770, Wong_2011_21409391, Kuusisto_2011_21356067, Garcia_2009_18302019, Aoude_2014_24949998, Ding_2011_20927582, Prokofyeva_2012_22310028, Hofstatter_2011_21365267, Papi_2010_19763884, Pakkanen_2009_20003494). The variant was also identified in the following databases: dbSNP (ID: rs45624036) as “With other allele”, ClinVar (12x, as benign GeneDx, Invitae, Prevention Genetics, ARUP, Ambry Genetics, Pathway Genetics, PALB2 database, and as likely benign by Cancer Genetics, Illumina, Institute for Biomarker; and ITMI with no indication of clinical significance), Clinvitae (4x, as benign with conflicting pathogenicity), LOVD 3.0 (18x), Zhejiang Colon Cancer Database (4x, as benign with conflicting pathogenicity). The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 1441 of 276692 chromosomes (4 homozygous) at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 31 of 23944 chromosomes (freq: 0.001295), “Other” in 30 of 6452 chromosomes (freq: 0.00465), Latino in 63 of 34386 chromosomes (freq: 0.001832), European Non-Finnish in 814 of 126400 chromosomes (freq: 0.00644), Ashkenazi Jewish in 43 of 10130 chromosomes (freq: 0.004245), European Finnish in 428 of 25784 chromosomes (freq: 0.0166), and South Asian in 32 of 30744 chromosomes (freq: 0.001041); while the variant was not observed in the East Asian, populations. The p.Val932Met 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 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000514905	SCV001744010	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000514905	SCV001797414	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121760	SCV001808313	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121760	SCV001906424	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514905	SCV001955682	likely benign	not provided		no assertion criteria provided	clinical testing