Submissions for variant NM_024675.4(PALB2):c.2228A>G (p.Tyr743Cys)

gnomAD frequency: 0.00002  dbSNP: rs141749524

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164010	SCV000214615	likely benign	Hereditary cancer-predisposing syndrome	2018-08-27	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	RCV000197626	SCV000253591	likely benign	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000197626	SCV000268010	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000255110	SCV000321926	likely benign	not provided	2019-12-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29802286, 26315354, 26283626, 29338689, 26411315, 25256751, 27621404, 28796317, 29667044, 32426482)
Illumina Laboratory Services, Illumina	RCV000164010	SCV000396098	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000296163	SCV000396099	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.
Color Diagnostics, LLC DBA Color Health	RCV000164010	SCV000902864	likely benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781684	SCV000919929	benign	not specified	2019-02-15	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2228A>G (p.Tyr743Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 313070 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0011 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Notably, the variant was detected at a frequency of 0.0170 in a large study of Japanese controls (Momozawa_2018), providing further supporting evidence for a benign role. c.2228A>G has been reported in the literature in individuals at risk or affected by Hereditary Breast and Ovarian Cancer or pancreatic ductal adenocarcinoma (Momozawa_2018, Ohmoto_2018, Takeuchi_2018, Sato_2017, Balmana_2016, Nakagomi_2015, Ramus_2015, Thompson, 2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a likely pathogenic variant has been reported in our internal database (MSH2 c.1511-1G>A). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030648	SCV001193678	likely benign	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781684	SCV002551666	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150010	SCV003838086	likely benign	Breast and/or ovarian cancer	2022-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255110	SCV004222287	likely benign	not provided	2023-08-09	criteria provided, single submitter	clinical testing