Submissions for variant NM_024675.4(PALB2):c.1379A>G (p.Gln460Arg)

gnomAD frequency: 0.00002  dbSNP: rs749494645

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166836	SCV000217650	likely benign	Hereditary cancer-predisposing syndrome	2021-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000989572	SCV000259919	likely benign	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000166836	SCV000396115	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000289282	SCV000396116	uncertain significance	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, 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.
GeneDx	RCV000483813	SCV000565348	uncertain significance	not provided	2022-03-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, gastric, or prostate cancer (Nakagomi 2016, Decker 2017, Chan 2018, Momozawa 2018, Suzuki 2020, Hata 2021, Hagio 2021); This variant is associated with the following publications: (PMID: 26411315, 27701467, 28796317, 28779002, 29338689, 32566746, 33414401, 34755017, 30093976, 32426482, 30287823, 34736091)
PreventionGenetics, part of Exact Sciences	RCV000483813	SCV000807073	uncertain significance	not provided	2017-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000166836	SCV000839039	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166836	SCV000910808	likely benign	Hereditary cancer-predisposing syndrome	2016-07-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780567	SCV000917953	benign	not specified	2021-10-05	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1379A>G (p.Gln460Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250890 control chromosomes, predominantly at a frequency of 0.00092 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 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.1379A>G has been reported in the literature predominantly in individuals of East Asian ancestry affected with breast and/or ovarian cancer without strong evidence for causality (example, Nakagomi_2016, Sato_2017, and Chan_2018). These reports 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 has been observed at our laboratory (CDH1 c.1565+2dupT), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven laboratories have classified the variant as variant of uncertain significance, three laboratories have classified the variant as likely benign and one laboratory have classified the variant Benign. Based on the evidence outlined above, the variant was classified as Benign.
Mendelics	RCV000989572	SCV001140038	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030716	SCV001193684	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000780567	SCV002067197	uncertain significance	not specified	2018-07-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000166836	SCV002530609	likely benign	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	curation
Leiden Open Variation Database	RCV000780567	SCV001193094	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.