ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2794G>A (p.Val932Met) (rs45624036)

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Total submissions: 25
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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.
Invitae RCV000114559 SCV000153851 benign Familial cancer of breast 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000116090 SCV000172810 benign Hereditary cancer-predisposing syndrome 2014-08-05 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
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,PreventionGenetics RCV000121760 SCV000314374 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV001282379 SCV000604595 benign none provided 2020-07-24 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 Health, Inc RCV000116090 SCV000685979 benign Hereditary cancer-predisposing syndrome 2014-11-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 Praxis fuer Humangenetik Tuebingen RCV000514905 SCV001150777 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
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
Human Genetics - Radboudumc,Radboudumc RCV000514905 SCV001955682 likely benign not provided no assertion criteria provided clinical testing

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