Submissions for variant NM_024675.4(PALB2):c.765T>C (p.Asp255=)

gnomAD frequency: 0.00006  dbSNP: rs45465299

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114662	SCV000261168	likely benign	Familial cancer of breast	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215345	SCV000275084	likely benign	Hereditary cancer-predisposing syndrome	2015-04-16	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.
Illumina Laboratory Services, Illumina	RCV000338727	SCV000396126	likely benign	Fanconi anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000215345	SCV000396127	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000590553	SCV000514023	likely benign	not provided	2021-06-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18302019, 17200668, 27535533)
Color Diagnostics, LLC DBA Color Health	RCV000215345	SCV000686075	benign	Hereditary cancer-predisposing syndrome	2016-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590553	SCV000699613	likely benign	not provided	2016-09-06	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.765T>C (p.Asp255Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a benign outcome for this substitution along with 5/5 in silico tools via Alamut predicting the variant not to have an impact on normal splicing. This variant was found in 17/124694 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0002248 (15/66738). This slightly exceeds the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was reported in breast cancer patients, however without strong evidence such as co-segregation; therefore these reports do not allow the establishment of a cause effect relationship between the variant and the disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as Likely Benign.
Counsyl	RCV000114662	SCV000786231	likely benign	Familial cancer of breast	2018-03-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590553	SCV000889595	likely benign	not provided	2023-06-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000215345	SCV002531219	likely benign	Hereditary cancer-predisposing syndrome	2021-11-22	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490768	SCV002796581	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149790	SCV003838780	likely benign	Breast and/or ovarian cancer	2021-12-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114662	SCV004019652	benign	Familial cancer of breast	2023-03-31	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.
Leiden Open Variation Database	RCV000114662	SCV001193016	likely benign	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590553	SCV001552120	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Asp255= variant was identified in 2 of 2036 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was present in 1 of 2168 control chromosomes (frequency: 0.0005) from healthy individuals (Garcia 2009, Rahman 2007). The variant was also identified in dbSNP (ID: rs45465299) as "With other allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, GeneDx and five other submitters), and in LOVD 3.0 (2X ). The variant was identified in control databases in 22 of 277172 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 22 of 126672 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asp255= 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000590553	SCV001905793	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590553	SCV001952575	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529926	SCV004721845	likely benign	PALB2-related disorder	2019-07-31	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).