Submissions for variant NM_024675.4(PALB2):c.2258G>A (p.Arg753Gln)

gnomAD frequency: 0.00001  dbSNP: rs587778586

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000121757	SCV000211514	likely benign	not specified	2018-01-17	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	RCV000195647	SCV000255084	likely benign	Familial cancer of breast	2023-12-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121757	SCV000596212	uncertain significance	not specified	2017-03-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561765	SCV000666872	likely benign	Hereditary cancer-predisposing syndrome	2018-07-16	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121757	SCV000699557	likely benign	not specified	2023-04-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2258G>A (p.Arg753Gln) 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 2.1e-05 in 282886 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2258G>A, has been reported in the literature in at least two individuals affected with breast cancer without strong evidence for causality (e.g., Dorling_2021, Guindalini_2022), however, the variant has also been found in several healthy controls (Bodian_2014, Momozawa_2018, Dorling_2021). In addition, a co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5130_5133delTGTA (p.Tyr1710X); internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=5) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000195647	SCV000786195	uncertain significance	Familial cancer of breast	2018-03-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000561765	SCV000839022	benign	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000561765	SCV000903011	likely benign	Hereditary cancer-predisposing syndrome	2015-11-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561765	SCV002530679	likely benign	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000195647	SCV004019685	likely benign	Familial cancer of breast	2024-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588075	SCV004222288	likely benign	not provided	2023-05-11	criteria provided, single submitter	clinical testing
ITMI	RCV000121757	SCV000085955	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV000588075	SCV001193203	uncertain significance	not provided	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.