Submissions for variant NM_024675.4(PALB2):c.2379C>T (p.Gly793=)

gnomAD frequency: 0.00009  dbSNP: rs377626805

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212811	SCV000149993	likely benign	not provided	2020-09-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26564480, 26283626, 24556926, 28779002, 31642931)
Ambry Genetics	RCV000116084	SCV000213044	likely benign	Hereditary cancer-predisposing syndrome	2018-06-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000200135	SCV000255086	benign	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000200135	SCV000268050	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000292657	SCV000396096	uncertain significance	Fanconi anemia complementation group N	2018-01-13	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.
Illumina Laboratory Services, Illumina	RCV000116084	SCV000396097	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116084	SCV000685946	likely benign	Hereditary cancer-predisposing syndrome	2018-05-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000116084	SCV000839021	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780574	SCV000917963	benign	not specified	2022-09-01	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2379C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site. However, these predictions have yet to be confirmed by functional studies. In contrast, one recently published functional study reported this variant among those with no impact on RNA splicing (Karam_2019). The authors considered the in-silico splicing predictions as a false positive evidence category and reported re-classifying this variant from a VUS to likely benign based on their study. The variant allele was found at a frequency of 7.4e-05 in 256744 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.4e-05 vs 0.00016), allowing no conclusion about variant significance. c.2379C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Catucci_2014, Damiola_2015, Thompson_2015, Borecka_2016, Decker_2017 etc.). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, this variant was found in four women in FLOSSIES database of cancer free women older than age 70, suggesting that the variant could be benignTo our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar classified as VUS (n=5), Likely Benign (n=6) and Benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000200135	SCV001140012	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116084	SCV002530694	likely benign	Hereditary cancer-predisposing syndrome	2021-06-27	criteria provided, single submitter	curation
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000200135	SCV002548550	likely benign	Familial cancer of breast	2022-05-15	criteria provided, single submitter	clinical testing	PALB2:c.2379C>T is present in 0.0081% in the large population studies (GnomAd). The deep exonic variant is predicted to create a de novo donor splice site in exon 5 by in silico splicing tools. Functional RNA study has shown that the variant causes an insignificant splicing aberration leading to out-of-frame transcript (PMID: 35806449, 31642931). Therefore the variant was classified as likely benign (ACMG/AMP: BS3-Stand alone, BS1, PP3).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212811	SCV004222301	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 35806449 (2022), 28779002 (2017), 26564480 (2015), 26283626 (2015), 24556926 (2014)) and pancreatic cancer (PMID: 27106063 (2016)). Experimental studies on PALB2 mRNA splicing report the variant has no significant effect on splicing, however additional studies are needed to determine the global effect of this variant on PALB2 function (PMIDs: 35806449 (2022), 31642931 (2019)). The frequency of this variant in the general population, 0.00011 (14/129160 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on PALB2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
CeGaT Center for Human Genetics Tuebingen	RCV000212811	SCV004701813	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PALB2: PP3, BS1:Supporting, BS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003945052	SCV004761558	likely benign	PALB2-related condition	2022-02-07	criteria provided, single submitter	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).
Leiden Open Variation Database	RCV000200135	SCV001193219	uncertain significance	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	RCV001354155	SCV001548698	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Gly793= variant was identified in 2 of 5146 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was not identified in 3996 control chromosomes from healthy individuals (Catucci 2014, Thompson 2015). The variant was also identified in dbSNP (ID: rs377626805) as "With other allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics and one clinical laboratory; as uncertain significance by five submitters), and in LOVD 3.0 (1x) database. The variant was identified in control databases in 22 of 277202 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 3 of 34412 chromosomes (freq: 0.00009), European in 15 of 126706 chromosomes (freq: 0.0001), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian, and Finnish, populations. The p.Gly793= 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. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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.