Submissions for variant NM_024675.4(PALB2):c.232G>A (p.Val78Ile)

gnomAD frequency: 0.00013  dbSNP: rs515726085

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587015	SCV000149992	likely benign	not provided	2021-02-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22241545, 23935836, 24949998, 26315354, 26564480, 26283626, 28717660, 28051113, 18302019, 26306225, 29458332, 31586400, 31636395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114522	SCV000166652	likely benign	Familial cancer of breast	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000116083	SCV000184261	likely benign	Hereditary cancer-predisposing syndrome	2019-03-27	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114522	SCV000267981	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587015	SCV000601756	likely benign	not provided	2020-09-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116083	SCV000685943	likely benign	Hereditary cancer-predisposing syndrome	2018-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212771	SCV000699562	likely benign	not specified	2023-10-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.232G>A (p.Val78Ile) 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 0.00012 in 257942 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.232G>A has been reported in the literature in individuals affected with HBOC or related cancer phenotypes (example, Bhai_2021, Blanco 2013, Damiola 2015, Thompson 2015, Tischkowitz 2012, Castellanos 2017), however, with limited information (i.e. lack of co-occurrence and/or cosegregation data). Moreover, the variant has been also reported in unaffected controls in some studies (Damiola 2015, Ramus 2015). One publication, which focuses on a family that has a history of melanoma, indicates the variant of interest to not segregate with disease (Aoude 2014); i.e. multiple family members are affected with melanomas that do not carry the variant of interest, along with unaffected family members carrying the variant. At least two publications report experimental evidence evaluating an impact on protein function (Rodrigue_2019, Wiltshire_2019). These results showed no damaging effect of this variant on BRCA1 and BRCA2 interaction and Homology directed repair activity (HDR). The following publications have been ascertained in the context of this evaluation (PMID: 24949998, 34326862, 23935836, 28051113, 26564480, 26315354, 31586400, 22241545, 31636395, 26283626). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely benign, n=10, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000114522	SCV001140057	likely benign	Familial cancer of breast	2024-04-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587015	SCV001961584	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587015	SCV002010969	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116083	SCV002530688	likely benign	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212771	SCV002760838	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149780	SCV003838719	likely benign	Breast and/or ovarian cancer	2021-10-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114522	SCV004931999	benign	Familial cancer of breast	2023-12-20	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Leiden Open Variation Database	RCV000587015	SCV001192953	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356931	SCV001552226	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Val78Ile variant was identified in 5 of 6906 proband chromosomes (frequency: 0.0007) from Spanish, Australian, Danish and American individuals or families with HBOC (BRCA1/BRCA2 negative breast cancers (with/without pancreatic cancer in the family)) or familial melanoma (Tischkowitz 2012, Thompson 2015, Blanco 2013, Aoude 2014). Segregation analysis in the familial melanoma study did not show cosegregation with disease, with 2 of 4 affected members carrying the variant. The variant was also identified in dbSNP (ID: rs515726085) as “other”, ClinVar (classified as uncertain significance by GeneDx, Invitae, PALB2 database, and likely benign by Ambry Genetics and Peter MacCallum Cancer Center Study), Clinvitae (with conflicting interpretations of pathogenicity) and (LOVD 3.0 (4X); and was not identified in Cosmic, MutDB, and Zhejiang Colon Cancer Database databases. The variant was identified in control databases in 30 (1 homozygous) of 272762 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val78 residue is not conserved in mammals and 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
PreventionGenetics, part of Exact Sciences	RCV004529921	SCV004119853	likely benign	PALB2-related disorder	2024-06-17	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).