Submissions for variant NM_024675.4(PALB2):c.1544A>G (p.Lys515Arg)

gnomAD frequency: 0.00009  dbSNP: rs515726072

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114479	SCV000166644	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129175	SCV000183910	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	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	RCV000114479	SCV000268001	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000586359	SCV000292648	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27328445, 29052111, 29338072, 26283626, 22241545, 21618343, 27616075, 25503501, 27930734, 21356067, 28873162, 27997549, 29522266, 31757951, 31159747)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586359	SCV000601732	uncertain significance	not provided	2021-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235723	SCV000699539	uncertain significance	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1544A>G (p.Lys515Arg) results in a conservative amino acid change located in the DNA-binding domain (DBD, Nepomuceno_2020) of 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 9.3e-05 in 257362 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), suggesting the variant may be a benign polymorphism found in the Latino subpopulation. c.1544A>G has been reported in the literature in individuals affected with cancer including Hereditary Breast and Ovarian Cancer and stomach adenocarcinoma but it was also reported in one healthy woman older than 50 years (Hauke_2018, He_2016, Hellebrand_2011, Kraus_2016, Lu_2015, Mandelker_2017, Maxwell_2014, Myszka_2017, Thompson_2015, Tischkowitz_2012, Tsaousis_2019, Akcay_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Moreover, the variant was reported in the FLOSSIES database in two women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. One co-occurrence with a pathogenic variant has been reported internally (APC c.4873delC, p.Gln1625fs*25; internal LCA database). At least one functional study reports this variant has slightly reducing HR activity and no effect on PARPi sensitivity compared to WT (Boonen_2019). Twelve ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=9) and as likely benign (n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneKor MSA	RCV000129175	SCV000822107	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129175	SCV000902883	likely benign	Hereditary cancer-predisposing syndrome	2015-07-21	criteria provided, single submitter	clinical testing
Mendelics	RCV004700413	SCV001140032	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586359	SCV002010981	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129175	SCV002530622	likely benign	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149776	SCV003838089	uncertain significance	Breast and/or ovarian cancer	2022-11-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528789	SCV000807076	uncertain significance	PALB2-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The PALB2 c.1544A>G variant is predicted to result in the amino acid substitution p.Lys515Arg. This variant has been previously reported in individuals with familial breast cancer (Thompson et al 2015. PubMed ID: 26283626; Kraus et al 2017. PubMed ID: 27616075). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and in ClinVar it is classified as likely benign and a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/126607/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV000114479	SCV001193118	uncertain significance	Familial cancer of breast	2019-12-04	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355376	SCV001550248	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The PALB2 p.Lys515Arg variant was identified in 6 of 10468 proband chromosomes (frequency: 0.00057) from individuals or families with breast or ovarian cancer and was not identified in 4896 control chromosomes from healthy individuals (Hellebrand 2011, Kraus 2017, Maxwell 2015, Myszka 2017, Thompson 2015, Tischkowitz 2012). The variant was also identified in dbSNP (ID: rs515726072) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, Genedx, PALB2 database and three clinical laboratories), MutDB , and in LOVD 3.0 (1x), databases. The variant was not identified in Cosmic, or Zhejiang University Database. The variant was identified in control databases in 23 of 277248 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.00016), Latino in 7 of 34418 chromosomes (freq: 0.0002), European in 15 of 126730 chromosomes (freq: 0.00012), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys515 residue is conserved in mammals but not in more distantly related organisms however 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.