Submissions for variant NM_024675.4(PALB2):c.84C>T (p.Tyr28=)

gnomAD frequency: 0.00001  dbSNP: rs761533286

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164145	SCV000214761	likely benign	Hereditary cancer-predisposing syndrome	2014-11-26	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.
Invitae	RCV000195762	SCV000253607	likely benign	Familial cancer of breast	2024-01-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000195762	SCV000487992	likely benign	Familial cancer of breast	2015-12-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000428315	SCV000514015	likely benign	not specified	2017-04-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000164145	SCV000537512	likely benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679774	SCV000807117	likely benign	not provided	2017-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000428315	SCV000917951	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164145	SCV002531231	likely benign	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316018	SCV004016507	likely benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000195762	SCV004019147	benign	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000428315	SCV004027095	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679774	SCV001548663	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Tyr28= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs761533286) “With Likely benign allele” and ClinVar (classified likely benign by Ambry Genetics, Invitae, GeneDx, Counsyl, Color and Prevention Genetics). The variant was identified in control databases in 3 of 246264 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33582 chromosomes (freq: 0.00003) and European Non-Finnish in 2 of 111714 chromosomes (freq: 0.00002), while not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Tyr28= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.