Submissions for variant NM_024675.4(PALB2):c.94C>G (p.Leu32Val)

gnomAD frequency: 0.00003  dbSNP: rs151316635

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656932	SCV000150026	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate PARPi sensitivity and BRCA1 interaction comparable to wild type (Rodrigue et al., 2019); Observed in individuals with personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (Teo et al., 2013; Maxwell et al., 2015; Thompson et al., 2015; Tung et al., 2015; Yurgelun et al., 2015; Maxwell et al., 2016; Decker et al., 2017); This variant is associated with the following publications: (PMID: 24728327, 27425854, 23448497, 25980754, 26283626, 25503501, 25186627, 28779002, 27153395, 28259476, 20871615, 19369211, 31586400, 33471991, 34687117)
Ambry Genetics	RCV000116117	SCV000185766	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.L32V variant (also known as c.94C>G), located in coding exon 2 of the PALB2 gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals diagnosed with breast cancer (Teo ZL et al. Breast Cancer Res. 2013 Feb 28;15:R17; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879). In one study, this alteration was reported in 6/13087 breast cancer cases and 1/5488 control individuals from the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). It was also reportedly detected in conjunction with a TP53 pathogenic mutation in an individual with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000114673	SCV000255117	likely benign	Familial cancer of breast	2024-01-27	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114673	SCV000267979	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114673	SCV000488135	uncertain significance	Familial cancer of breast	2016-01-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656932	SCV000601801	uncertain significance	not provided	2020-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116117	SCV000902879	likely benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001119845	SCV001278291	uncertain significance	Fanconi anemia complementation group N	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121744	SCV001372423	likely benign	not specified	2020-06-08	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.94C>G (p.Leu32Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (gnomAD). c.94C>G has been reported in the literature in individuals affected with breast cancer and Lynch syndrome but also, in controls (e.g. Maxwell_2015, Teo_2013, Thompson_2015, Tung_2015, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a TP53 pathogenic variant (c.733G>A, p.G245S) has been reported in a patient with breast cancer (Maxwell_2015). Another study reported the variant in one heterozygous individual at high risk for breast and/or ovarian cancer with a classification of Likely benign, using lack of segregation in affected family members as evidence (Maxwell_2016). Experimental evidence evaluating an impact on protein function demonstrated the variant has similar activity to wild-type (Rodrigue_2019). Altogether, these data provide supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; uncertain significance, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000121744	SCV002065318	uncertain significance	not specified	2021-05-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.94C>G, in exon 2 that results in an amino acid change, p.Leu32Val. This sequence change has been described in gnomAD with a frequency of 0.004% in the African-American sub-population (dbSNP rs151316635). The p.Leu32Val change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu32Val substitution. This sequence change has been reported in multiple individuals affected with breast cancer (PMID: 23448497, 25503501, 26283626). In one study, an individual with early onset breast cancer was also found to be a carrier of a pathogenic TP53 sequence change (PMID: 25503501). Additionally, the PALB2 Leu32Val variant has been identified in two individuals undergoing multigene panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (PMID: 25980754). Functional studies evaluating impact on protein function demonstrated that this variant has similar activity to wild-type (PMID: 31586400). Based on the currently available evidences, the clinical significance of the p.Leu32Val change remains unknown at this time.
Sema4, Sema4	RCV000116117	SCV002531240	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114673	SCV004019638	benign	Familial cancer of breast	2023-03-31	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656932	SCV004227547	uncertain significance	not provided	2022-07-20	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV003905094	SCV004722698	uncertain significance	PALB2-related condition	2024-01-25	criteria provided, single submitter	clinical testing	The PALB2 c.94C>G variant is predicted to result in the amino acid substitution p.Leu32Val. This variant was identified in an individual suspected of having Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). It has also been identified in several individuals affected with breast cancer (Teo et al. 2013. PubMed ID: 23448497; Table S1, Maxwell et al. 2015. PubMed ID: 25503501; Table S4, Maxwell et al. 2016. PubMed ID: 27153395; Thompson et al. 2015. PubMed ID: 26283626; supplementary data, Tung et al. 2015. PubMed ID: 25186627). However, no further information was provided regarding its pathogenicity or segregation with disease in families. This variant was also identified in a healthy individual with no history of cancer (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126781/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000121744	SCV000085942	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV000656932	SCV001192923	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	RCV001357251	SCV001552667	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu32Val variant was identified in 6 of 12886 proband chromosomes (frequency: 0.00047) from individuals or families with breast cancer or Lynch syndrome and was present in 10 of 5358 control chromosomes (frequency: 0.002) from healthy individuals (Maxwell 2015, Teo 2013, Thompson 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs151316635) as "With Likely benign,other allele ", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, PALB2 database and one clinical laboratory; as likely benign by one clinical laboratory) , MutDB , LOVD 3.0 (3x), and in Zhejiang University Database (1x). The variant was not identified in Cosmic, database. The variant was identified in control databases in 5 of 277244 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), European in 4 of 126730 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu32 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) 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.