Submissions for variant NM_024675.4(PALB2):c.899C>T (p.Thr300Ile)

gnomAD frequency: 0.00001  dbSNP: rs528541334

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114669	SCV000219156	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114669	SCV000267992	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Ambry Genetics	RCV000219489	SCV000275228	likely benign	Hereditary cancer-predisposing syndrome	2018-09-27	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.
Counsyl	RCV000114669	SCV000487873	uncertain significance	Familial cancer of breast	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001284670	SCV000520763	likely benign	not provided	2020-11-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23977390, 24728327, 21113654, 26283626, 30309218, 31636395)
Color Diagnostics, LLC DBA Color Health	RCV000219489	SCV000910878	benign	Hereditary cancer-predisposing syndrome	2016-10-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284670	SCV001470588	likely benign	not provided	2020-03-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121751	SCV002071277	uncertain significance	not specified	2019-10-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219489	SCV002531233	benign	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121751	SCV003928582	likely benign	not specified	2023-04-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114669	SCV004019663	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. 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].
ITMI	RCV000121751	SCV000085949	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354467	SCV001549092	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Thr300Ile variant was identified in 3 of 2516 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Ding 2011, Phuah 2013, Thompson 2015). The variant was also identified in the following databases: dbSNP (ID: rs528541334) as “With Uncertain significance allele”, in ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx; classified as uncertain significance by Ambry Genetics, Counsyl, PALB2 database, CGLPMCCC), Clinvitae, and LOVD 3.0. The variant was not identified in Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in control databases in 110 of 277114 chromosomes (1 homozygous) at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Other in 1 of 6462 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 106 of 30778 chromosomes (freq: 0.003); it was not observed in the European, Ashkenazi Jewish, or Finnish populations. The p.Thr300 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.