Submissions for variant NM_024675.4(PALB2):c.344G>T (p.Gly115Val)

gnomAD frequency: 0.00009  dbSNP: rs145598272

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114628	SCV000166663	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000165559	SCV000216292	likely benign	Hereditary cancer-predisposing syndrome	2018-09-10	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114628	SCV000267983	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114628	SCV000488594	uncertain significance	Familial cancer of breast	2016-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000589320	SCV000516979	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23824750, 26564480, 18053174, 26283626, 26689913)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589320	SCV000601786	likely benign	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589320	SCV000699598	likely benign	not provided	2016-08-08	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.344G>T (p.Gly115Val) variant involves the alteration of a non-conserved nucleotide. The altered amino acid is not located in any known domain. 4/5 in silico tools predict a benign outcome for this variant. This variant was found in 26/139488 control chromosomes at a frequency of 0.0001864, which is slightly higher than the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this variant is possibly a benign polymorphism. This variant has been reported in HBOC patients and matched controls. At least one study suggested that this variant was not associated with the disease (Foulkes_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003891592	SCV000807110	likely benign	PALB2-related condition	2021-02-08	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).
Color Diagnostics, LLC DBA Color Health	RCV000165559	SCV000911009	benign	Hereditary cancer-predisposing syndrome	2015-08-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149789	SCV003838718	likely benign	Breast and/or ovarian cancer	2021-06-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114628	SCV004019615	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].
CeGaT Center for Human Genetics Tuebingen	RCV000589320	SCV004033467	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Leiden Open Variation Database	RCV000114628	SCV001192964	likely benign	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	RCV001357627	SCV001553151	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Gly115Val variant was identified in 3 of 5070 proband chromosomes (frequency: 0.0006) from individuals or families with breast or ovarian cancer and was present in 17 of 18204 control chromosomes (frequency: 0.0009) from healthy individuals (Foulkes 2007, Wong-Brown 2014, Thompson 2015, Damiola 2015). The variant was also identified in dbSBP (ID: rs145598272) as “With other allele”, ClinVar (3x likely benign by Invitae, Ambry Genetics, GeneDx, 3x uncertain significance by Peter MacCallum Cancer Centre, PALB2 database, Counsyl), Clinvitae (3x likely benign by GeneDx, Ambry Genetics, Invitae; 3x uncertain significance by PALB2 database, Counsyl, Peter MacCallum Cancer Centre), LOVD 3.0 (2x effect unknown), Zhejiang Colon Cancer Database (2x pathogenicity unknown), databases. The variant was not identified in COSMIC or MutDB databases. The variant was identified in control databases in 25 of 276102 chromosomes (22x European non-Finnish, 2x Latino, 1x African) at a frequency of 0.00009 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Gly115Val residue is not conserved in mammals and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.