Submissions for variant NM_024675.4(PALB2):c.2200A>T (p.Thr734Ser)

gnomAD frequency: 0.00007  dbSNP: rs45543843

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586054	SCV000149990	uncertain significance	not provided	2025-02-23	criteria provided, single submitter	clinical testing	Observed in multiple individuals with breast or pancreatic cancer (PMID: 20091115, 22241545, 25186627, 26898890, 28767289, 34326862); Observed at comparable frequencies in control populations and in individuals with breast, ovarian, or other cancers (PMID: 17200668, 26315354, 26283626, 28779002, 29641532, 32546565); Published functional studies suggest no damaging effect: HDR activity comparable to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 17200668, 20091115, 26283626, 25186627, 22241545, 26315354, 28779002, 28767289, 28440294, 28873162, 29641532, 32659497, 32546565, 22941656, 34326862, 31636395, 37937776)
Ambry Genetics	RCV000116081	SCV000186205	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.T734S variant (also known as c.2200A>T), located in coding exon 5 of the PALB2 gene, results from an A to T substitution at nucleotide position 2200. The threonine at codon 734 is replaced by serine, an amino acid with similar properties. This variant has been identified in numerous disease cohorts as well and unaffected control groups across studies (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Sauty de Chalon A et al. Breast Cancer Res. Treat. 2010 May;121:253-5; Thompson ER et al. Breast Cancer Res, 2015 Aug;17:111; Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Caminsky NG et al. Hum Mutat, 2016 07;37:640-52; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Wiltshire T et al. Genet. Med., 2019 Oct). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114515	SCV000255083	likely benign	Familial cancer of breast	2025-01-29	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114515	SCV000268009	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114515	SCV000489313	uncertain significance	Familial cancer of breast	2016-09-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116081	SCV000685928	likely benign	Hereditary cancer-predisposing syndrome	2024-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855600	SCV000699556	likely benign	not specified	2024-09-26	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2200A>T (p.Thr734Ser) 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 0.00018 in 1626984 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016). c.2200A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rahman_2007, Sauty de Chalon_2010, Tischkowitz_2012,Tung_2014, Thompson_2015, Ramus_2015, Caminsky_2016, Shindo_2017, Lattimore_2021, Bhai_2021) . These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (CHEK2 c.1100delC, p.T367fs*15 (internal testing); BRCA2 c.1929delG, p.Arg645fsX15 (Tung_2014); NBN c.127C>T, p.Arg43X and MUTYH c.1187-2A>G (Bhai_2021)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed the variant to have proficient HDR activity, providing supporting evidence for a benign role (Wiltshire_2020). The following publications have been ascertained in the context of this evaluation (PMID: 26898890, 33471991, 33113089, 17200668, 26315354, 20091115, 28767289, 26283626, 22241545, 25186627, 31636395, 34326862). ClinVar contains an entry for this variant (Variation ID: 126640). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586054	SCV001469595	uncertain significance	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116081	SCV002530673	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114515	SCV004019630	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
Baylor Genetics	RCV000114515	SCV004202003	uncertain significance	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114515	SCV001193193	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	RCV001356351	SCV001551496	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358251	SCV001553929	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance.